Maryland Pesticide Network

Recent Research

Ann Epidemiol. 2002 Aug;12(6):389-94.

Pesticide poisoning and depressive symptoms among farm residents.

Stallones L, Beseler C.

Department of Psychology, Colorado Injury Control Research Center, Colorado State University, Fort Collins, CO 80523-1776, USA.

PURPOSE: The purpose of the study presented is to evaluate the association between pesticides and depressive symptoms among a population exposed to chemicals as a result of agricultural use. Chronic sequelae of acute pesticide poisoning from organophosphate compounds may include anxiety and depression. In some states, farmers have been reported to have higher rates of depression than other population groups. Little work has been done to describe the effects of exposure to organophosphate compounds and depressive symptoms among the farming population.

METHODS: Data for this study came from a cross sectional survey of farmers and their spouses conducted in an eight county area in northeastern Colorado. Personal interviews were conducted with the study participants. Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression (CES-D) scale. Pesticides applied on the farms were assessed using self-reported questionnaires. Conditional logistic regression was used to model the relationship between depression and pesticide-related illness in a stratified analysis.

RESULTS: Between 1992-1997, 761 individuals were enrolled in this cross sectional survey. Adjusting for a number of potential confounders, the odds ratio for depression associated with pesticide-related illness was 5.87 [95% confidence interval (CI) = 2.56-13.44].

CONCLUSIONS: Exposure to pesticides at a high enough concentration to cause self reported poisoning symptoms was associated with high depressive symptoms independently of other known risk factors for depression among farm residents.

PMID: 12160597 [PubMed - indexed for MEDLINE]

Ann Epidemiol. 2008 Oct;18(10):768-74. Epub 2008 Aug 9.

A cohort study of pesticide poisoning and depression in Colorado farm residents.

Beseler CL, Stallones L.

Department of Epidemiology, Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198-4395, USA. cbeseler@unmc.edu.

PURPOSE: Depressive symptoms have been associated with pesticide poisoning among farmers in cross-sectional studies, but no longitudinal studies have assessed the long-term influence of poisoning on depressive symptoms. The purpose of this study was to describe the associations between pesticide poisoning and depressive symptoms in a cohort of farm residents.

METHODS: Farm operators and their spouses were recruited in 1993 from farm truck registrations using stratified probability sampling. The Center for Epidemiologic Studies-Depression scale was used to evaluate depression in participants using generalized estimating equations. Baseline self-reported pesticide poisoning was the exposure of interest in longitudinal analyses.

RESULTS: Pesticide poisoning was significantly associated with depression in three years of follow-up after adjusting for age, gender, and marital status (odds ratio [OR] 2.59; 95% confidence interval [CI] 1.20-5.58). Depression remained elevated after adjusting for health, decreased income, and increased debt (OR 2.00; CI 0.91-4.39) and was primarily due to significant associations with the symptoms being bothered by things (OR 3.29; CI 1.95-5.55) and feeling everything was an effort (OR 1.93; CI 1.14-3.27).

CONCLUSIONS: Feeling bothered and that everything was an effort were persistently associated with a history of pesticide poisoning, supportive of the hypothesis that prolonged irritability may result from pesticide poisoning.

PMID: 18693039 [PubMed - indexed for MEDLINE]

Environ Health Perspect. 2008 December; 116(12): 1713–1719. Published online 2008 September 9. doi: 10.1289/ehp.11091.
PMCID: PMC2599768

Copyright: This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose.

Research

Depression and Pesticide Exposures among Private Pesticide Applicators Enrolled in the Agricultural Health Study

Cheryl L. Beseler,1,2,3 Lorann Stallones,1 Jane A. Hoppin,4 Michael C.R. Alavanja,5 Aaron Blair,5 Thomas Keefe,6 and Freya Kamel41 Colorado Injury Control Research Center, Department of Psychology, Colorado State University, Fort Collins, Colorado, USA2 Epidemiology Department, College of Public Health3 Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, Nebraska, USA4 Epidemiology Branch, National Institutes of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA5 Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, USA6 Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, USAAddress correspondence to C.L. Beseler, College of Public Health, University of Nebraska Medical Center, 984395 UNMC, Omaha, NE 68198-4395 USA. Telephone: (402) 559-3976. Fax: (402) 559-7259. E-mail: cbeseler/at/unmc.edu

The authors declare they have no competing financial interests.

Received November 20, 2007; Accepted September 9, 2008.

Abstract

Background

We evaluated the relationship between diagnosed depression and pesticide exposure using information from private pesticide applicators enrolled in the Agricultural Health Study between 1993 and 1997 in Iowa and North Carolina.

Methods

There were 534 cases who self-reported a physician-diagnosed depression and 17,051 controls who reported never having been diagnosed with depression and did not feel depressed more than once a week in the past year. Lifetime pesticide exposure was categorized in three mutually exclusive groups: low (< 226 days, the reference group), intermediate (226–752 days), and high (> 752 days). Two additional measures represented acute high-intensity pesticide exposures: an unusually high pesticide exposure event (HPEE) and physician-diagnosed pesticide poisoning. Logistic regression analyses were performed relating pesticide exposure to depression.

Results

After adjusting for state, age, education, marital status, doctor visits, alcohol use, smoking, solvent exposure, not currently having crops or animals, and ever working a job off the farm, pesticide poisoning was more strongly associated with depression [odds ratio (OR) = 2.57; 95% confidence interval (CI), 1.74–3.79] than intermediate (OR = 1.07; 95% CI, 0.87–1.31) or high (OR = 1.11; 95% CI, 0.87–1.42) cumulative exposure or an HPEE (OR = 1.65; 95% CI, 1.33–2.05). In analysis of a subgroup without a history of acute poisoning, high cumulative exposure was significantly associated with depression (OR = 1.54; 95% CI, 1.16–2.04).

Conclusion

These findings suggest that both acute high-intensity and cumulative pesticide exposure may contribute to depression in pesticide applicators. Our study is unique in reporting that depression is also associated with chronic pesticide exposure in the absence of a physician-diagnosed poisoning.Keywords: cumulative exposure, depression, farm applicators, pesticides, pesticide poisoning 

W.H.O.

Pesticide exposure and suicidal ideation in rural communities in Zhejiang province, China

Jianmin Zhang a, Robert Stewart b, Michael Phillips c, Qichang Shi a & Martin Prince b

a. Office of Mental Health, Zhejiang Provincial Tongde Hospital, Hangzhou, China.
b. Institute of Psychiatry, King's College London (Institute of Psychiatry), De Crespigny Park, London, SE5 8AF, England.
c. WHO Collaborating Center for Research and Training in Suicide Prevention, Beijing Hui Long Guan Hospital, Beijing, China.

Correspondence to Robert Stewart (e-mail: r.stewart@iop.kcl.ac.uk).

(Submitted: 18 April 2008 – Revised version received: 10 December 2008 – Accepted: 23 January 2009 – Published online: 28 July 2009.)

Bulletin of the World Health Organization 2009;87:745-753. doi: 10.2471/BLT.08.054122

Introduction

The use and availability of pesticides are significant concerns in the field of mental health, not only because these chemicals are used in suicide attempts1 but also because their possession may be directly associated with mental disorder. Suicide rates are reported to be higher in areas where organophosphates are used2 and exposure is a possible risk factor for Parkinson disease3,4 and Alzheimer disease,3 for depressive and anxiety disorders5,6 and for mortality ascribed to mental disorder.7 However, research in this area remains controversial.8,9 Pesticides have been widely used in agriculture since the 1950s10 but, despite precautionary measures, intentional and occupational poisoning remain major concerns. For example, pesticide ingestion was implicated in 62% of suicides in China between 1996 and 2000, which corresponds to around 175 000 cases per year.1,11

Suicide in China accounts for 44% of all suicides worldwide.12 Moreover, suicide is the fifth leading cause of death in China13 overall and the leading cause in 15–34-year-olds.14 In rural areas, suicide rates are 2–5 times those in urban areas13,15 and, in contrast to Western populations, the rate is higher in women than men.13 Although mental disorder, especially depression, is associated with suicide,16 the link between suicide and mental disorder may be relatively weak in China.13 The reasons for the high rate and unique pattern of suicide in China have yet to be established.

Organophosphate pesticides are used widely in China and the potential for exposure is high. Despite this, the mental health risks of prolonged exposure remain unclear. We investigated the association between the storage of pesticides at home and recent suicidal ideation in rural China by analysing data from a province-wide survey of mental disorders that was carried out in 2001 as part of a WHO and Chinese Ministry of Health project.

Methods

The study was performed in Zhejiang province, a densely populated coastal province of China that in 2000 had a total population of 45 million, 70% of which lived in rural areas. It is one of the most developed provinces in China and in 2000 had an average per capita gross domestic product (GDP) of 13 461 renminbi (US$ 1660), the fourth highest among China's 31 provinces and independent municipalities.

Sample size

The survey was designed to ascertain a prevalence of mental disorder of 15% with 1% precision. In addition, the sample size was increased to 15 000 to enable comparisons to be made according to gender and urban or rural residence. The ratio of urban to rural residence was estimated to be 1:2.17

Sampling procedure

The survey employed a multistage sampling process that has previously been described in detail by Shi et al.18 The sampling frame was the province-wide computerized household registry, which was updated during the 2000 national census. Seven indicators (i.e. population density, birth rate, the proportion of non-agricultural labourers, per capita GDP, illiteracy rate, crude death rate and proportion aged > 65 years) for 11 cities and 63 rural counties were subjected to a principal components factor analysis. Two factors accounted for 65.2% of the variance. The factor scores were then used to construct five strata: (i) 5 cities (comprising 45.5% of the total urban population); (ii) 6 cities (comprising 54.5% of the total urban population); (iii) 19 counties (comprising 30.2% of the total rural population); (iv) 13 counties (comprising 20.6% of the total rural population); and (v) 31 counties (comprising 49.2% of the total rural population). This analysis considered only the three rural strata, which broadly corresponded to mountain, plains and coastal regions.

Groups of three, two and five counties were selected from the three rural strata (mountain, plains and coastal regions, respectively) by sampling in proportion to the population aged 15 years or over. Thereafter, five districts within each county and, subsequently, two villages within each district were sampled in proportion to their populations. Systematic random sampling was used in each stratum to select the counties, districts, and villages. A total of 100 villages were selected from the 50 rural districts sampled from the 10 counties. The final stage of sampling, which was again carried out in proportion to population size, involved the identification of 1000 residents aged 15 years or more in each of the 10 counties. At each village, simple random selection was used to identify target subjects from the computerized registry of community residents. The demographic characteristics of the selected population sample were similar to those of the province as a whole.17 At each village, a 20% supplemental sample was also selected using the same method.

During the survey at least three attempts were made to contact selected individuals but 3372 (22.5%) could not be contacted, primarily because of non-residence. A similar proportion of men and women (i.e. 22.6% and 22.4%, respectively) could not be contacted, and these individuals were, on average, 5 years younger than those who could be contacted: mean age 39.3 years and 44.3 years, respectively. People of a similar age and gender to replace the 3372 individuals who could not be located were randomly selected from three sources: the supplemental sample at that location (n = 567), neighbouring households of the target subjects (n = 2133) and, for two sites at which most residents had relocated, neighbouring communities (n = 672).

Assessments

Interviews were carried out in study participants' homes by 34 trained psychiatric nurses between September and December 2001. All participants provided verbal informed consent after the study had been fully explained. Local ethics review boards were not in place at the time of the survey. According to standard practice at that time, the survey was initially considered and approved by WHO and further consideration and approval were then provided by the Department of Disease Control and the Department of International Cooperation at the Chinese Ministry of Health, as well as by the Mental Health Leading Group of Zhejiang province. The principal independent variable considered in this analysis was the storage of pesticides at home. In households where informants reported storing pesticides (excluding rodenticides), the type of pesticide and method of storage were recorded.

All participants were asked the following questions: "Have you ever considered suicide or deliberate self-harm in your lifetime?", "Have you ever planned suicide or deliberate self-harm in your lifetime?", and "Have you ever attempted suicide or deliberate self-harm in your lifetime?". If any of the above were answered positively, further questions were asked about the respondent's age at the first and most recent episode or occurrence. The primary dependent variable was whether or not the respondent reported suicidal ideation in the 2 years before the interview. No participant reported attempting or planning suicide without previous suicidal ideation.

The Chinese version of the 12-item General Health Questionnaire (GHQ) was administered to all participants and a cut-off score of 3/12 was used to define GHQ caseness,19 which was treated as a covariate. This instrument was translated into Chinese and validated in the 1980s20,21 and has been widely used. Recent specific ethnographic evaluation has supported its applicability in a rural Chinese context.22 Other covariates were age, sex, years of formal education, marital status, annual per capita household income (in three strata), family history of suicidal behaviour, and subjective global physical health status in the prior month, which was categorized on a 5-point scale and then dichotomized to "poor health" versus "others". The rural stratum of the participant was also considered as a covariate and as an effect modifier. For unadjusted analyses, the three rural strata were ordered according to the frequency of suicidal ideation, although this ordering differed from that of the socioeconomic indices (i.e. the order of areas with ascending socioeconomic indices were mountain followed by coastal followed by plains regions).

Statistical analysis

Statistical weighting was applied so that the participants selected accurately represented the total population of Zhejiang province. Within each cluster (i.e. each village), the initial weight was the number of individuals in the population represented by the cluster divided by the number of completed interviews in that cluster. Thus, the weight incorporated an adjustment for individuals included in a sample but not interviewed. In addition, weights were further adjusted to reduce the effect of extreme weights: in clusters in which the weight was greater than two standard deviations above the average weight, the value was reduced to equal two standard deviations. Finally, post-stratification weights were obtained to compensate for any mismatch between the age and gender distributions of each stratum and the age and gender distributions of individuals aged 15 years or more in Zhejiang province. Post-stratification weights that took design effects and clustering into account were used in the analysis. Standard errors were adjusted for unequal sampling fractions within each stratum and for possible homogeneity within each cluster. The analysis employed the complex survey procedures in SPSS 15.0 statistical software (SPSS Inc., Chicago, Illinois, United States of America). Logistic regression analysis was used to examine the relationships between suicidal ideation in the prior 2 years, reported storage of pesticides in the home, and other covariates.

Results

Of the 10 035 individuals in the selected sample from the 10 rural counties, 9811 (97.8%) completed the interview. The 224 who did not complete the interview included 202 who refused to participate, 17 who were unable to participate because of severe illness or intervening mortality and 5 who completed only part of the interview. Among those who did complete it, 7627 (77.7%) were from the original sample and 2184 (22.3%) were replacements from the sources described above.

Of the 9811 respondents, 5116 (52.1%) stored pesticides in the home. Among the 5088 who reported the method of storage, 249 (4.9%) locked up the pesticides, 1588 (31.2%) stored them in a high location not easily accessible by children, and 3251 (63.9%) stored them where they were easily accessible by all household residents. Of the pesticides stored at home, 86.9% comprised or included organophosphates. The most commonly stored pesticide was methamidophos, which was present in 63.4% of households that stored pesticides.

Self-report lifetime prevalence estimates of suicidal ideation, planning suicide and attempting suicide in the 9811 respondents were 4.8%, 0.9% and 0.4%, respectively. Prevalence estimates for the most recent 2 years were 2.0%, 0.4% and 0.2%, respectively. To avoid potential misclassification of cases, the 270 individuals who only reported suicidal ideation more than 2 years previously were excluded. This left 9541 participants. Moreover, the analysis was further restricted to 9159 participants for whom complete data on all covariates were available.

Associations between pesticide storage at home and demographic, socioeconomic and clinical covariates, adjusted for design effects and clustering only, are summarized in Table 1. The presence of pesticides at home was significantly associated with male gender, older age, fewer years of education, lower income, current or previous marriage, a family history of suicidal behaviour and GHQ caseness. Significant differences were also found between the three regions.

Table 1. Associations between pesticide storage at home and demographic, socioeconomic and clinical characteristics, Zhejiang province, China, 2001 [html 9kb]

Associations between suicidal ideation in the 2 years prior to the study and pesticide storage and demographic, socioeconomic and clinical covariates, adjusted for design effects and clustering only, are summarized in Table 2. The odds ratio (OR) for the association between pesticides stored at home and suicidal ideation over the prior 2 years was 2.40 (95% confidence interval, CI: 1.68–3.43). Suicidal ideation was also significantly associated with pesticide storage method, female gender, older age, fewer years of education, lower income, poor physical health, a family history of suicidal behaviour and GHQ caseness, and was significantly different between the three regions.

Table 2. Associations between suicidal ideation in the 2 years prior to the study and pesticide storage and participants' demographic, socioeconomic and clinical characteristics, Zhejiang province, China, 2001 [html 11kb]

In the logistic regression models, suicidal ideation in the prior 2 years remained significantly associated with pesticide storage at home. As shown in Table 3, the unadjusted OR for the association between pesticides stored at home and suicidal ideation over the prior 2 years was 2.12 (95% CI: 1.54–2.93). Adjustment for only design effects and clustering had a minor effect on the estimated OR, which became 2.40 (95% CI: 1.68–3.43). The only substantial change in the OR of interest occurred following adjustment for the rural stratum. After full adjustment (i.e. model 11 in Table 3), the ORs for suicidal ideation for different storage methods compared to no storage at home were as follows: for locked storage, 1.13 (95% CI: 0.32–4.00); for unlocked high-up storage, 1.40 (95% CI: 0.86–2.25); and for easy access, 1.76 (95% CI: 1.18–2.59).

Table 3. Logistic regression analysis of the association between pesticide storage at home and suicidal ideation in the 2 years prior to the study showing adjustments for potential confounding factors, Zhejiang province, China, 2001 [html 5kb]

Further analyses were carried out separately for the three rural strata (Table 4). After full adjustment, a significant association between pesticide storage at home and suicidal ideation was found in the plains region but not in the mountain or coastal region. Finally, analyses were repeated using all (i.e. not just recent) suicidal ideation as an outcome and home storage of organophosphates as the only exposure. Overall, there was no meaningful change in the associations of interest (data not shown).

Table 4. Associations between pesticide storage at home and suicidal ideation in the 2 years prior to the study in three rural strata corresponding to mountain, coastal and plains regions, Zhejiang province, China, 2001 [html 4kb]

Discussion

We found a positive, independent association between the presence of pesticides in the home and suicidal ideation in the prior 2 years in a large representative sample of the rural population of Zhejiang province, China. We also found that reported suicidal ideation became more common with increasing ease of access to pesticides and, furthermore, that the highest prevalence of reported suicidal ideation was in the two rural strata (i.e. the plains and mountain regions) with the highest prevalence of pesticide storage at home.

The strong points of this study are that it involved a large, representative sample and that the response rate was high, both of which indicate that the results can be readily applied to the source population.

An important limitation is that individual pesticide exposure was not directly measured. Chronic low level exposure to pesticides is difficult to ascertain directly, particularly in a large-scale community study where biological assays are not feasible. Occupational exposure is also difficult to ascertain because of the near universal use of pesticides in agriculture. We therefore had to use self-report data on home storage as a proxy measure of exposure. Pesticide storage is not a sensitive issue in these communities so it is unlikely that respondents intentionally underreported home storage or that their reports were influenced by the presence or absence of previous suicidality. Moreover, measurement inaccuracy would have the effect of diluting the association of interest. Similarly, although prior suicidal thoughts may be underreported, underreporting is unlikely to vary with respect to pesticide storage. If the associations described here do indeed relate to an individual's level of pesticide exposure rather than stem from reverse causality or unmeasured confounding, the true association between suicidality and underlying exposure is likely to be substantially stronger than that estimated here using the proxy measure.

With respect to confounding, the logistic regression analysis showed that none of the covariates accounted substantially for the association identified between exposure to pesticides and suicidal ideation. However, it should be borne in mind that physical and mental health were assessed relatively briefly and additional research is required to clarify potential mediating and confounding effects further. Although the GHQ has been translated into Chinese and validated in Chinese populations, it may nonetheless underestimate mental distress since it makes use of a 12-point scale that cannot encompass all forms of psychopathology, such as the expression of emotional distress through somatic complaints, which has been observed in Chinese populations.23

The cross-sectional nature of the study does not enable the direction of cause and effect to be definitively inferred. It is possible that the possession of pesticides was a consequence of suicidal ideation, although we think that this is unlikely for the following reasons: (i) the hypothesized outcome was rare compared with pesticide exposure; (ii) the association between pesticide storage at home and suicidal ideation was independent of GHQ status; (iii) the association of interest was little affected by whether suicidal ideation throughout life or in the previous 2 years was defined as the outcome; and (iv) the association increased with ease of pesticide access.

Pesticide possession was frequent in this population and many of the commonly stored pesticides contained methamidophos, an organophosphate insecticide that persists in water and soil following contamination and that has been classified by WHO as a class‑I pesticide (i.e. extremely or highly toxic). In addition, the liquid preparation used in agriculture is volatile, making it particularly hazardous.24 The assumption underlying our analysis is that participants who keep pesticides at home will have experienced higher chronic low-level exposure, principally through transdermal or respiratory absorption, possibly during storage but more likely due to increased use or spillage. While biologically plausible, the association between home storage and the level of individual exposure has not, to our knowledge, been directly demonstrated, although home storage has been cited as an undesirable potential source of exposure.25 Most studies have focused on occupational use as a proxy for chronic low-level exposure and have compared high- and low-exposure workers. This is not feasible in rural China because of the homogeneity of occupation. One study found higher levels of urine metabolites in children from communities where pesticides were used and stored,26 suggesting that exposure may take a wide variety of routes. However, home storage cannot definitively be implicated and it is possible that exposure could occur through contamination of clothing or other fabrics or deficient pesticide preparation practices.

Several studies have indicated that pesticide use is associated with neurological disorders and worse mental health3–6 as well as with suicidal thoughts and behaviour.2 There are a variety of potential causal mechanisms. Imbalance in cholinergic pathways are implicated in depressive disorder27 and organophosphates, including methamidophos, inhibit cholinesterase activity.28 Paraoxonase activity may be a modifying factor since paraoxonase is known to hydrolyse a wide variety of organophosphates and plays a role in their detoxification.29,30

Although chronic exposure to organophosphates may increase suicide through increasing depressive symptoms,2 a large number of people in China who develop suicidal thoughts or who complete suicide do not have an apparent mental illness.13,31 There may, therefore, be different aetiological mechanisms. The ready availability of highly lethal means could, for example, convert impulsive, low-intent suicide "attempts" among persons without a mental illness into completed suicides.32 Suicidality may be a separate symptom domain independent of depression,33 and it has been suggested that some risk factors for suicidality do not act through increasing depression.34–37 Frontal lobe syndromes and increased impulsivity would be one example of an alternative causal pathway. The observation that adjustment for GHQ score did not affect the association of interest may reflect this; however, as highlighted earlier, some aspects of depressive symptomatology may not be adequately identified by this instrument in the Chinese population.

The findings of this study might partially account for the much higher incidence of suicide in rural than urban areas of China. The observed association in our study between pesticide storage in different regions and suicidal ideation in those regions is interesting. Less easy to explain are the apparent differences in the association of interest between regions. They require further replication and evaluation. The direction of cause and effect also requires further research that makes use of more accurate markers of chronic exposure. Regardless of the direction of causation, the association between pesticide exposure and suicidality demonstrates that potentially vulnerable groups with previous suicidal thoughts have increased access to highly toxic chemicals. This is of particular concern in China and other agriculture-based Asian and Pacific nations where suicidal behaviour is often related to impulsivity and the ready availability of a lethal method.12,13

The influence of pesticide exposure on mental disorder, suicide and overall health is a very important public health issue. To address this, in 2006 three WHO departments announced a global public health initiative and released a report on community interventions for safer access to pesticides.38 It is vital that these messages are disseminated as widely as possible to the appropriate policy-makers. ■

Acknowledgements

We thank the staff of the Zhejiang Office of Mental Health, participating nurses and doctors from psychiatric hospitals in the province for their assistance in data collection and entry, and Mark Davies for his assistance in the statistical analysis.

Funding: The survey was part of a WHO and Chinese Ministry of Health Mental Health Project and was supported by a WHO grant (GL/GLO/MNH/343/XE/00.J.999.00). Dr Zhang prepared this paper at King's College London while supported by a Chevening Scholarship from the British Council and by a grant from the Institute of Social Psychiatry, London, United Kingdom. Robert Stewart is funded by a National Institute for Health Research Specialist Biomedical Research Centre for Mental Health award to the South London and Maudsley NHS Foundation Trust, and the Institute of Psychiatry, King's College London, United Kingdom. Michael Phillips is also affiliated with the Department of Psychiatry and Department of Epidemiology, Columbia University, United States of America.

Competing interests: None declared.

References

doi:10.1016/j.aquatox.2009.08.001
Copyright © 2009 Published by Elsevier B.V.

Widespread occurrence of intersex in black basses (Micropterus spp.) from U.S. rivers, 1995–2004

Jo Ellen Hincka, , email, Vicki S. Blazerb, Christopher J. Schmitta, Diana M. Papouliasa and Donald E. Tillitta

aU.S. Geological Survey (USGS), Columbia Environmental Research Center (CERC), 4200 New Haven Rd., Columbia, MO 65201, USA

bNational Fish Health Research Laboratory, USGS Leetown Science Center, 11649 Leetown Rd., Kearneysville, WV 24530, USA

Received 10 June 2009;  revised 29 July 2009;  accepted 6 August 2009.  Available online 13 August 2009.

Abstract

Intersex occurrence in freshwater fishes was evaluated for nine river basins in the United States. Testicular oocytes (predominantly male testes containing female germ cells) were the most pervasive form of intersex observed, even though similar numbers of male (n = 1477) and female (n = 1633) fish were examined. Intersex was found in 3% of the fish collected. The intersex condition was observed in four of the 16 species examined (25%) and in fish from 34 of 111 sites (31%). Intersex was not found in multiple species from the same site but was most prevalent in largemouth bass (Micropterus salmoides; 18% of males) and smallmouth bass (M. dolomieu; 33% of males). The percentage of intersex fish per site was 8–91% for largemouth bass and 14–73% for smallmouth bass. The incidence of intersex was greatest in the southeastern United States, with intersex largemouth bass present at all sites in the Apalachicola, Savannah, and Pee Dee River Basins. Total mercury, trans-nonachlor, p,p′-DDE, p,p′-DDD, and total PCBs were the most commonly detected chemical contaminants at all sites, regardless of whether intersex was observed. Although the genotype of the intersex fish was not determined, the microscopic appearance of the gonads, the presence of mature sperm, and the concentrations of sex steroid hormones and vitellogenin indicate the intersex bass were males. Few reproductive endpoints differed significantly among male and intersex bass; plasma vitellogenin concentration in males was not a good indicator of intersex presence. Hierarchical linkages of the intersex condition to reproductive function will require a more quantitative measure of intersex (e.g. severity index) rather than presence or absence of the condition. The baseline incidence of intersex gonadal tissue in black basses and other freshwater fishes is unknown, but intersex prevalence may be related to collection season, age, and endocrine active compounds in the environment. Intersex was not found in largemouth bass older than five years and was most common in 1–3-year-old male largemouth bass. The cause(s) of intersex in these species is also unknown, and it remains to be determined whether the intersex we observed in largemouth and smallmouth bass developed during sex differentiation in early life stages, during exposure to environmental factors during adult life stages, or both.

Keywords: Endocrine disruption; Ovotestis; Fishes; Environment; Estrogenic

Well-Water Consumption and Parkinson's Disease in Rural California

Formal Correction: This article has been formally corrected to address the following errors.

    Nicole M. Gatto1, Myles Cockburn2, Jeff Bronstein3, Angelika D. Manthripragada1, Beate Ritz1,3,4

    1 Department of Epidemiology, University of California–Los Angeles, Los Angeles, California, USA, 2 Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA, 3 Department of Neurology, and, 4 Department of Environmental Health Sciences, University of California–Los Angeles, Los Angeles, California, USA

    Abstract 

    Introduction: Investigators have hypothesized that consuming pesticide-contaminated well water plays a role in Parkinson's disease (PD), and several previous epidemiologic studies support this hypothesis.

    Objectives: We investigated whether consuming water from private wells located in areas with documented historical pesticide use was associated with an increased risk of PD.

    Methods: We employed a geographic information system (GIS)–based model to estimate potential well-water contamination from agricultural pesticides among 368 cases and 341 population controls enrolled in the Parkinson's Environment and Genes Study (PEG). We separately examined 6 pesticides (diazinon, chlorpyrifos, propargite, paraquat, dimethoate, and methomyl) from among 26 chemicals selected for their potential to pollute groundwater or for their interest in PD, and because at least 10% of our population was exposed to them.

    Results: Cases were more likely to have consumed private well water and to have consumed it on average 4.3 years longer than controls (p 0.02). High levels of possible well-water contamination with methomyl [odds ratio (OR) = 1.67; 95% confidence interval (CI), 1.00–2.78]), chlorpyrifos (OR = 1.87; 95% CI, 1.05–3.31), and propargite (OR = 1.92; 95% CI, 1.15–3.20) resulted in approximately 70–90% increases in relative risk of PD. Adjusting for ambient pesticide exposures only slightly attenuated these increases. Exposure to a higher number of water-soluble pesticides and organophosphate pesticides also increased the relative risk of PD.

    Conclusion: Our study, the first to use agricultural pesticide application records, adds evidence that consuming well water presumably contaminated with pesticides may play a role in the etiology of PD.

    Agrichemicals in surface water and birth defects in the United States

    Paul D Winchester 1 , Jordan Huskins 2 , Jun Ying 3
    1.Section of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 2.Indiana University School of Medicine, Indianapolis, IN, USA 3.Institute for the Study of Health, University of Cincinnati, Cincinnati, OH, USA

    Correspondence


    Paul D Winchester, MD, St. Francis Hospital, 8111 South Emerson Avenue, Indianapolis, IN 46237, USA.
    Tel: 1 317 865 5595 |
    Fax: 1 317 865 5148 |
    Email: paul.winchester@ssfhs.org

    Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

    Copyright Journal Compilation © 2009 Foundation Acta Pædiatrica

    KEYWORDS
    Atrazine • Birth defects • Nitrates • Pesticides

    ABSTRACT

    To investigate if live births conceived in months when surface water agrichemicals are highest are at greater risk for birth defects.

    Monthly concentrations during 1996–2002 of nitrates, atrazine and other pesticides were calculated using United States Geological Survey's National Water Quality Assessment data. Monthly United States birth defect rates were calculated for live births from 1996 to 2002 using United States Centers for Disease Control and Prevention natality data sets. Birth defect rates by month of last menstrual period (LMP) were then compared to pesticide/nitrate means using logistical regression models.

    Mean concentrations of agrichemicals were highest in April–July. Total birth defects, and eleven of 22 birth defect subcategories, were more likely to occur in live births with LMPs between April and July. A significant association was found between the season of elevated agrichemicals and birth defects.

    Elevated concentrations of agrichemicals in surface water in April–July coincided with higher risk of birth defects in live births with LMPs April–July. While a causal link between agrichemicals and birth defects cannot be proven from this study an association might provide clues to common factors shared by both variables.

    Received
    1 October 2008; revised 25 November 2008; accepted 15 December 2008.

    DIGITAL OBJECT IDENTIFIER (DOI)10.1111/j.1651-2227.2008.01207.x About DOI

    August 2009

    Poisoning the Well: How the EPA is Ignoring Atrazine Contamination in Surface and Drinking Water in the Central United States

    Authors
    Mae Wu, Mayra Quirindongo, Jennifer Sass, Andrew Wetzler

    Executive Summary

    Banned in the European Union and clearly linked to harm to wildlife and potentially to humans, the pesticide atrazine provides little benefit to offset its risks. In this report, NRDC brings together for the first time the results of surface water and drinking water monitoring required by the U.S. EPA to create a more comprehensive analysis of atrazine pollution across the Midwestern and Southern United States. We found that the U.S. EPA’s inadequate monitoring systems and weak regulations have compounded the problem, allowing levels of atrazine in watersheds and drinking water to peak at extremely high concentrations. Given the pesticide’s limited usefulness and the ease with which safer agricultural methods can be substituted to achieve similar results, NRDC recommends phasing out the use of atrazine, more effective atrazine monitoring, the adoption of farming techniques that can help minimize the use of atrazine and prevent it from running into waterways, and the use of home filtration systems by consumers.

    Environmental Toxicology and Chemistry, Vol. 28, No. 9, pp. 2004—2008, 2009 © 2009 SETAC
    Printed in the USA
    0730-7268/09 $12.00 + .00

    THE TOXICITY OF ROUNDUP ORIGINAL MAX® TO 13 SPECIES OF LARVAL AMPHIBIANS

    RICK A. RELYEA* and DEVIN K. JONES
    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA

    (Received 17 January 2009; Accepted 23 April 2009)

    Abstract—With the increased use of glyphosate-based herbicides (marketed under several names, including Roundup® and Vision®), there has been a concomitant increased concern about the unintended impacts that particular formulations containing the popular surfactant polyethoxylated tallowamine (POEA) might have on amphibians. Published studies have examined a relatively small number of anuran species (primarily from Australia and eastern North America) and, surprisingly, no species of salamanders. Using a popular formulation of glyphosate (Roundup Original Max®), the goal of the present study was to conduct tests of lethal concentrations estimated to kill 50% of a population after 96 h (LC5096-h) on a wider diversity of species from both eastern and western North America. Tests were conducted on nine species of stage 25, larval anurans from three families (Ranidae: Rana pipiens, R. clamitans, R. sylvatica, R. catesbeiana, R. cascadae; Bufonidae: Bufo americanus, B. boreas; and Hylidae: Hyla versicolor, Pseudacris crucifer) and four species of larval salamanders from two families (Ambystomatidae: Ambystoma gracile, A. maculatum, A. laterale; and Salamandridae: Notophthalmus viridescens). For the nine species of larval anurans, LC5096-h values ranged from 0.8- to 2.0-mg acid equivalents per liter with relatively little pattern in differential sensitivity among the species or families. The four species of larval salamanders were less sensitive than the anurans, with LC5096-h values ranging from 2.7- to 3.2-mg acid equivalents per liter and no substantial differences among the species of salamanders. This work substantially increases the available data on amphibian sensitivity to glyphosate formulations that include either POEA surfactants or the equally moderately to highly toxic surfactants of Roundup Original Max and should be useful for improving future risk assessments. Keywords—Tadpole Caudata Ecotoxicology Nontarget Pesticide

    * To whom correspondence may be addressed (relyea@pitt.edu). Published on the Web 4/30/2009. 2004

    Evidence for inhibition of cholinesterases in insect and mammalian nervous systems by the insect repellent deet

    Vincent Corbel, Maria Stankiewicz, Cedric Pennetier, Didier Fournier, Jure Stojan, Emmanuelle Girard, Mitko Dimitrov, Jordi Molgo, Jean Marc Hougard and Bruno Lapied

    BMC Biology 2009, 7:47doi:10.1186/1741-7007-7-47

    Published:5 August 2009

    Abstract (provisional)

    Background

    N,N-Diethyl-3-methylbenzamide (deet) remains the gold standard for insect repellents. About 200 million people use it every year and over 8 billion doses have been applied over the past 50 years. Despite the widespread and increased interest in the use of deetin public health programmes, controversies remain concerning both the identification of its target sites at the olfactory system and its mechanism of toxicity in insects, mammals and humans. Here, we investigated the molecular target site for deet and the consequences of its interactions with carbamate insecticides on the cholinergic system.

    Results

    By using toxicological, biochemical and electrophysiological techniques, we show that deet is not simply a behaviour-modifying chemical but that it also inhibits cholinesterase activity, in both insect and mammalian neuronal preparations. Deet is commonly used in combination with insecticides and we show that deet has the capacity to strengthen the toxicity of carbamates, a class of insecticides known to block acetylcholinesterase.

    Conclusion

    These findings question the safety of deet, particularly in combination with other chemicals, and they highlight the importance of a multidisciplinary approach to the development of safer insect repellents for use in public health.

    Therapeutic Drug Monitoring:

    August 2009 - Volume 31 - Issue 4 - pp 495-501

    doi: 10.1097/FTD.0b013e3181aae982
    Original Article

    Pediatric Acute Lymphoblastic Leukemia and Exposure to Pesticides

    Soldin, Offie P PhD, MBA; Nsouly-Maktabi, Hala PhD; Genkinger, Jeanine M PhD; Loffredo, Christopher A PhD; Ortega-Garcia, Juan Antonio MD; Colantino, Drew MBA; Barr, Dana B PhD; Luban, Naomi L MD; Shad, Aziza T MD; Nelson, David MD, MPH

    Abstract

    Organophosphates are pesticides ubiquitous in the environment and have been hypothesized as one of the risk factors for acute lymphoblastic leukemia (ALL). In this study, we evaluated the associations of pesticide exposure in a residential environment with the risk for pediatric ALL. This is a case-control study of children newly diagnosed with ALL, and their mothers (n = 41 child-mother pairs) recruited from Georgetown University Medical Center and Children's National Medical Center in Washington, DC, between January 2005 and January 2008. Cases and controls were matched for age, sex, and county of residence. Environmental exposures were determined by questionnaire and by urinalysis of pesticide metabolites using isotope dilution gas chromatography-high-resolution mass spectrometry. We found that more case mothers (33%) than controls (14%) reported using insecticides in the home (P < 0.02). Other environmental exposures to toxic substances were not significantly associated with the risk of ALL. Pesticide levels were higher in cases than in controls (P < 0.05). Statistically significant differences were found between children with ALL and controls for the organophosphate metabolites diethylthiophosphate (P < 0.03) and diethyldithiophosphate (P < 0.05). The association of ALL risk with pesticide exposure merits further studies to confirm the association.

    © 2009 Lippincott Williams & Wilkins, Inc.

    `

    ENVIRONMENTAL HEALTH PERSPECTIVES

    Synergistic Disruption of External Male Sex Organ Development by a Mixture of Four Antiandrogens

    Sofie Christiansen1^), Martin Scholze2^), Majken Dalgaard 1), Anne Marie Vinggaard1), Marta Axelstad 1), Andreas Kortenkamp 2*), and Ulla Hass 1*)

    1) National Food Institute, Technical University of Denmark Dept. of Toxicology and Risk Assessment Mørkhøj Bygade 19 DK-2860 Søborg Denmark Tel.: +45 72 34 75 44

    2) The School of Pharmacy University of London 29-39 Brunswick Square London WC1N 1AX United Kingdom Tel.: +44 20 7753 5908 *) Correspondence should be addressed to Andreas Kortenkamp, fax number +44 20 77535811, email address andreas.kortenkamp@pharmacy.ac.uk

    *) Correspondence should be addressed to Andreas Kortenkamp, fax number +44 20 77535811, email address andreas.kortenkamp@pharmacy.ac.uk

    ^ Both authors contributed equally.

    Abstract

    Background: By disrupting the action of androgens during gestation, certain chemicals present in food, consumer products and the environment can induce irreversible demasculinisation and malformations of sex organs among male offspring. However, the consequences of simultaneous exposure to such chemicals are not well described, especially when they exert their actions by differing molecular mechanisms. Objectives: To fill this gap, we investigated the effects of mixtures of a widely used plasticizer, di(2-ethylhexyl) phthalate (DEHP), two fungicides present in food, vinclozolin and prochloraz, and a pharmaceutical, finasteride, on landmarks of male sexual development in the rat, including changes in anogenital distance, retained nipples, sex organ weights and malformations of genitalia. These chemicals were chosen because they disrupt androgen action according to differing mechanisms of action.

    Results: Strikingly, the effect of combined exposure to the selected chemicals on malformations of external sex organs was synergistic, and the observed responses were greater than would be predicted from the toxicities of the individual chemicals. In relation to other hallmarks of disrupted male sexual development, including changes in anogenital distance, retained nipples, and sex organ weights, the combined effects were dose additive. When the four chemicals were combined at doses equal to no-observed-adverseeffect levels estimated for nipple retention, significant reductions in anogenital distance were observed in male offspring.

    Conclusions: Since unhindered androgen action is essential for human male development in foetal life, these findings are highly relevant to human risk assessment. Evaluations that ignore the possibility of combination effects may lead to considerable underestimations of risks associated with exposures to chemicals that disrupt male sexual differentiation.

    Environmental Toxicology and Chemistry, Vol. 28, No. 9, pp. 1939–1945, 2009
    © 2009 SETAC
    Printed in the USA
    0730-7268/09 $12.00 + .00

    VERY HIGHLY TOXIC EFFECTS OF ENDOSULFAN ACROSS NINE SPECIES OF TADPOLES: LAG EFFECTS AND FAMILY-LEVEL SENSITIVITY

    DEVIN K. JONES, JOHN I. HAMMOND, and RICK A. RELYEA*

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA

     

    (Received 23 January 2009; Accepted 2 April 2009)

    Abstract—Pesticides are commonly used for health and economic benefits worldwide, but increased use has led to increased contamination of aquatic habitats. To understand potential impacts on nontarget organisms in these habitats, toxicologists generally use short-term (4-d) toxicity tests on model organisms. For most pesticides, few amphibian tests have been conducted, but there is growing concern about the potential impact of pesticides to amphibian populations. For the insecticide endosulfan, previous studies have found that low concentrations can be very highly toxic to amphibians and have suggested that this mortality may exhibit important lag effects. To estimate the lethal concentration of endosulfan that would cause 50% mortality after 4 d (LC504-d) across a diversity of amphibians and the presence of lag effects, LC504-d experiments were conducted on nine species of tadpoles from three families (Bufonidae: Bufo americanus, B. boreas; Hylidae: Pseudacris crucifer, P. regilla, Hyla versicolor; and Ranidae: Rana pipiens, R. clamitans, R. cascadae, R. catesbeiana) and then held the animals for an additional 4 d in clean water. The LC504-d values for endosulfan ranged from 1.3 to 120 ppb, which classifies endosulfan as highly toxic to very highly toxic. Moreover, holding the animals for an additional 4 d in clean water revealed significant additional mortality in three of the nine species. Leopard frogs, for example, experienced no significant death during the initial 4-d exposure to 60 ppb but 97% death after an additional 4 d in clean water. A phylogenetic pattern also appears to exist among families, with Bufonidae being least susceptible, Hylidae being moderately susceptible, and Ranidae being most susceptible. Results from the present study provide valuable data to assess the impact of endosulfan on a globally declining group of vertebrates.

    Keywords—Ecotoxicology     Amphibian      decline      Nontarget      Anuran      Contaminant

    * To whom correspondence may be addressed (relyea@pitt.edu). Published on the Web 4/9/2009. 1939

    Published online July 20, 2009
    PEDIATRICS (doi:10.1542/peds.2008-3506)

    Prenatal Airborne Polycyclic Aromatic Hydrocarbon Exposure and Child IQ at Age 5 Years

    Frederica P. Perera, DrPHa,b, Zhigang Li, MPSa,b,c, Robin Whyatt, DrPHa,b, Lori Hoepner, MPHa,b, Shuang Wang, PhDa,b,c, David Camann, MSd and Virginia Rauh, ScDa,b

    aDepartment of Environmental Health Sciences,
    bColumbia Center for Children's Environmental Health, and
    cDepartment of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York;
    dSouthwest Research Institute, San Antonio, Texas

    Objective

    This study evaluated the relationship between prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAHs) and child intelligence.

    Methods

    Children of nonsmoking black or Dominican-American women residing in New York City were monitored from in utero to 5 years of age, with determination of prenatal PAH exposure through personal air monitoring for the mothers during pregnancy. At 5 years of age, intelligence was assessed for 249 children by using the Wechsler Preschool and Primary Scale of Intelligence-Revised. Multivariate linear regression models were used to estimate and to test the associations between prenatal PAH exposure and IQ.

    Results

    After adjustment for maternal intelligence, quality of the home caretaking environment, environmental tobacco smoke exposure, and other potentially confounding factors, high PAH levels (above the median of 2.26 ng/m3) were inversely associated with full-scale IQ (P = .007) and verbal IQ (P = .003) scores. Children in the high-exposure group had full-scale and verbal IQ scores that were 4.31 and 4.67 points lower, respectively, than those of less-exposed children ≤2.26 ng/m3). The associations between logarithmically transformed, continuous, PAH levels and these IQ measures also were significant (full-scale IQ: β = –3.00; P = .009; verbal IQ: β = –3.53; P = .002).

    Conclusion

    These results provide evidence that environmental PAHs at levels encountered in New York City air can affect children's IQ adversely.

    Key Words: prenatal * fetal * polycyclic aromatic hydrocarbons * air pollution * IQ

    Abbreviations: ETS, environmental tobacco smoke

    Accepted Mar 25, 2009.

    Environmental Toxicology and Chemistry

    Article: pp. 1696–1703 | Abstract | PDF (86K)

    TOXICITY OF TWO INSECTICIDES TO CALIFORNIA, USA, ANURANS AND ITS RELEVANCE TO DECLINING AMPHIBIAN POPULATIONS

    Donald W. Sparling1 and Gary M. Fellers2

    1. Cooperative Wildlife Research Laboratory, Southern Illinois University, Carbondale, Illinois 62901, USA, 2. U.S. Geological Survey, Western Ecology Research Center, Pt. Reyes National Seashore, Pt. Reyes, California 94956

    Contaminants have been associated with population declines of several amphibian species in California (USA). Pesticides from the Central Valley of California are transported by winds into the Sierra Nevada Mountains and precipitate into wet meadows where amphibians breed. The present study examined the chronic toxicity of two of the insecticides most commonly used in the Central Valley and found in the mountains, chlorpyrifos and endosulfan, to larval Pacific treefrogs (Pseudacris regilla) and foothill yellow-legged frogs (Rana boylii) and discusses the implications of this toxicity to declining amphibian populations. Larvae were exposed to the pesticides from Gosner stages 25 to 26 through metamorphosis. The estimated median lethal concentration (LC50) for chlorpyrifos was 365 μg/L in P. regilla and 66.5 μg/L for R. boylii. Time to metamorphosis increased with concentration of chlorpyrifos in both species, and cholinesterase activity declined with exposure concentration in metamorphs of both species at Gosner stages 42 to 46. For endosulfan, the estimated LC50 was 15.6 μg/L for P. regilla and 0.55 μg/L for R. boylii. All R. boylii exposed to concentrations of greater than 0.8 μg/L died before they entered metamorphosis. Pseudacris regilla remains relatively abundant and is broadly distributed throughout California. In contrast, R. boylii is among the species experiencing severe population declines. The present study adds to the increasing evidence that pesticides are very harmful to amphibians living in areas that are miles from sources of pesticide application.

    Keywords: Endosulfan, Chlorpyrifos, Amphibian population declines, Rana boylii, Pseudacris regilla

    Received: 21 July 2008; Accepted: 13 February 2009

    DOI: 10.1897/08-336.1

    Parental Exposure to Pesticides and Childhood Brain Cancer: United States Atlantic Coast Childhood Brain Cancer Study

    Youn K. Shim, Steven P. Mlynarek, and Edwin van Wijngaarden
    doi: 10.1289/ehp.0800209 (available at http://dx.doi.org/)
    Online 13 February 2009

    ABSTRACT:

    BACKGROUND: The etiology of childhood brain cancer remains largely unknown. However, previous studies have yielded suggestive associations with parental pesticide use.

    OBJECTIVES: We aimed to evaluate parental exposure to pesticides at home and on the job in relation to the occurrence of brain cancer in children.

    METHODS: We included one-to-one matched 526 case-control pairs. Brain cancer cases were diagnosed at <10 years of age and were identified from statewide cancer registries of four Atlantic Coast states of the United States. Controls were selected by random digit dialing. We conducted computer-assisted telephone interviews with mothers. Using information on residential pesticide use and jobs held by fathers during the 2-year period before the child's birth, we assessed potential exposure to insecticides, herbicides, and fungicides. For each job, two raters independently classified the probability and intensity of exposure; 421 pairs were available for final analysis. We calculated odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression, after adjustment for maternal education.

    RESULTS: A significant risk of astrocytoma was associated with exposures to herbicides from residential use (OR = 1.9; 95% CI = 1.2–3.0). Combining parental exposures to herbicides from both residential and occupational sources, the elevated risk remained significant (OR=1.8; 95% CI=1.1–3.1). Little association with primitive neuroectodermal tumors (PNET) was observed for any of the pesticide classes or exposure sources considered.

    CONCLUSIONS: Our observation is consistent with a previous literature reporting suggestive associations between parental exposure to pesticides and risk of astrocytoma in offspring but not PNET. However, these findings should be viewed in light of limitations in exposure assessment and effective sample size.

    Parkinson's Disease and Residential Exposure to Maneb and Paraquat From Agricultural Applications in the Central Valley of California

    Sadie Costello, Myles Cockburn, Jeff Bronstein, Xinbo Zhang and Beate Ritz

    Correspondence to Dr. Sadie Costello, Department of Environmental Health Sciences, School of Public Health, University of California, Berkeley, 50 University Hall, #7360, Berkeley, CA 94720-7360 (e-mail: sadie{at}berkeley.edu).

    Evidence from animal and cell models suggests that pesticides cause a neurodegenerative process leading to Parkinson's disease (PD). Human data are insufficient to support this claim for any specific pesticide, largely because of challenges in exposure assessment. The authors developed and validated an exposure assessment tool based on geographic information systems that integrated information from California Pesticide Use Reports and land-use maps to estimate historical exposure to agricultural pesticides in the residential environment. In 1998–2007, the authors enrolled 368 incident PD cases and 341 population controls from the Central Valley of California in a case-control study. They generated estimates for maneb and paraquat exposures incurred between 1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence interval (CI): 1.13, 2.73). Persons aged ≤60 years at the time of diagnosis were at much higher risk when exposed to either maneb or paraquat alone (odds ratio = 2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio = 4.17, 95% CI: 1.15, 15.16) in 1974–1989. This study provides evidence that exposure to a combination of maneb and paraquat increases PD risk, particularly in younger subjects and/or when exposure occurs at younger ages.

    case-control studies; fungicides, industrial; geographic information systems; herbicides; maneb; paraquat; Parkinson disease; pesticides

    Abbreviations: CI, confidence interval; DDE, dichlorodiphenyldichloroethylene; GIS, geographic information system; MPP+, toxic metabolite of 1-methyl-4-phenylpyridinium; OR, odds ratio; PD, Parkinson's disease; PLSS, Public Land Survey System; PUR, Pesticide Use Reporting

    Pesticide exposure resulting from treatment of lice infestation in school-aged children in Georgia

    References and further reading may be available for this article. To view references and further reading you must purchase this article.

    Luke P. Naehera, b, Dana B. Barrc, Corresponding Author Contact Information, E-mail The Corresponding Author, Nancy Rithmired, Jeannie Edwardse, Adrianne K. Holmesa, Larry L. Needhamc and Carol S. Rubina

    aDivision of Environmental Hazards and Health Effects, Centers for Disease Control and Prevention, National Center for Environmental Health, Atlanta, GA, USA

    bThe University of Georgia, College of Public Health, Department of Environmental Health Science, Athens, GA, USA

    cDivision of Laboratory Sciences, Centers for Disease Control and Prevention, National Center for Environmental Health, Atlanta, GA, USA

    dForsyth County School District, Cumming, GA, USA

    eDawson County School District, Dawsonville, GA, USA


    Received 16 June 2008;  accepted 5 September 2008.  Available online 22 October 2008.

    Abstract

    Objective

    The objective of this study was to assess pesticide exposures in children being treated for head lice with either lindane or permethrin (exposed group) and children who did not have a lice infestation and thus were not being treated with chemicals for head lice or scabies (unexposed group).

    Methods

    In 2001, we enrolled 78 children aged 6–10 years old and collected baseline urine samples and demographic information from all the children. We subsequently collected post-exposure urine samples and questionnaire information about lice treatment from the 29 (37%) children (exposed children) who had been diagnosed and were being treated for head lice. Metabolites of the pesticides lindane and permethrin were measured in the samples.

    Results

    The mean age of exposed and unexposed children in the study population was 9.3 years and 8.5 years, respectively. Fourteen of the 29 exposed children used prescription lice treatments (i.e., lindane or malathion); 25 of the 29 exposed children used at least one over-the-counte permethrin treatment, either alone or in addition to prescription treatments. Exposed children in both counties had higher urinary pyrethroid metabolite levels in their post-exposure samples compared with their baseline samples. However this difference was only significant in Forsyth County children.

    Conclusions

    The significantly increased post-exposure pyrethroid metabolite levels in the urine of Forsyth County children suggest that the children are exposed to pyrethroid insecticides through the use of lice shampoos.

    Keywords: Children; Pesticide; Lindane; Permethrin; Pyrethroid; Biomonitoring; Lice

    The Rise in Autism and the Role of Age at Diagnosis

    [Early Development: Original Article]

    Hertz-Picciotto, Irvaa,b; Delwiche, Loraa

    From the aDepartment of Public Health Sciences, University of California, Davis, California; and bMedical Investigations of Neurodevelopmental Disorders (M.I.N.D.) Institute, Sacramento, California.

    Submitted 11 July 2007; accepted 2 June 2008.

    Supported by grants from the National Institute of Environmental Health Sciences 1P01-ES11269, 2P01-ES11269, 1R01-ES015359 and by the Medical Investigations of Neurodevelopmental Disorders (M.I.N.D.) Institute.

    Correspondence: Irva Hertz-Picciotto, Professor, Department of Public Health Sciences, Deputy Director, Center for Children's Environmental Health, Building MS1C, University of California, Davis, CA 95616. E-mail: ihp@ucdavis.edu.

    Abstract

    Background: Autism prevalence in California, based on individuals eligible for state-funded services, rose throughout the 1990s. The extent to which this trend is explained by changes in age at diagnosis or inclusion of milder cases has not been previously evaluated.

    Methods: Autism cases were identified from 1990 through 2006 in databases of the California Department of Developmental Services, which coordinates services for individuals with specific developmental disorders. The main outcomes were population incident cases younger than age 10 years for each quarter, cumulative incidence by age and birth year, age-specific incidence rates stratified by birth year, and proportions of diagnoses by age across birth years.

    Results: Autism incidence in children rose throughout the period. Cumulative incidence to 5 years of age per 10,000 births rose consistently from 6.2 for 1990 births to 42.5 for 2001 births. Age-specific incidence rates increased most steeply for 2- and 3-year olds. The proportion diagnosed by age 5 years increased only slightly, from 54% for 1990 births to 61% for 1996 births. Changing age at diagnosis can explain a 12% increase, and inclusion of milder cases, a 56% increase.

    Conclusions: Autism incidence in California shows no sign yet of plateauing. Younger ages at diagnosis, differential migration, changes in diagnostic criteria, and inclusion of milder cases do not fully explain the observed increases. Other artifacts have yet to be quantified, and as a result, the extent to which the continued rise represents a true increase in the occurrence of autism remains unclear.

    Statistical Modelling Suggests That Anti-Androgens in Wastewater Treatment Works Effluents are Contributing Causes of Widespread Sexual Disruption in Fish Living in English Rivers

    Susan Jobling, Robert W. Burn, Karen Thorpe, Richard Williams, and Charles Tyler

    Abstract
    Abstract in PDF

    This EHP-in-Press article has been peer-reviewed, revised, and accepted for publication. The EHP-in-Press articles are completely citable using the assigned DOI code for the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process. Environ Health Perspect doi:10.1289/ehp.0800197 available via http://dx.doi.org/ [Online 7 January 2009]


    The full version of this article is available for free in PDF format.

    Prepared as part of the National Water-Quality Assessment Program, Source Water-Quality Assessment

    Anthropogenic Organic Compounds in Source Water of Nine Community Water Systems that Withdraw from Streams, 2002–05

    By James A. Kingsbury, Gregory C. Delzer, and Jessica A. Hopple

    Abstract

    Source water, herein defined as stream water collected at a water-system intake prior to water treatment, was sampled at nine community water systems, ranging in size from a system serving about 3,000 people to one that serves about 2 million people. As many as 17 source-water samples were collected at each site over about a 12-month period between 2002 and 2004 for analysis of 258 anthropogenic organic compounds. Most of these compounds are unregulated in drinking water, and the compounds analyzed include pesticides and selected pesticide degradates, gasoline hydrocarbons, personal-care and domestic-use compounds, and solvents. The laboratory analytical methods used in this study have relatively low detection levels—commonly 100 to 1,000 times lower than State and Federal standards and guidelines for protecting water quality. Detections, therefore, do not necessarily indicate a concern to human health but rather help to identify emerging issues and to track changes in occurrence and concentrations over time.

    About one-half (134) of the compounds were detected at least once in source-water samples. Forty-seven compounds were detected commonly (in 10 percent or more of the samples), and six compounds (chloroform, atrazine, simazine, metolachlor, deethylatrazine, and hexahydrohexamethylcyclopentabenzopyran (HHCB) were detected in more than one-half of the samples. Chloroform was the most commonly detected compound—in every sample (year round) at five sites. Findings for chloroform and the fragrances HHCB and acetyl hexamethyl tetrahydronaphthalene (AHTN) indicate an association between occurrence and the presence of large upstream wastewater discharges in the watersheds. The herbicides atrazine, simazine, and metolachlor also were among the most commonly detected compounds. Degradates of these herbicides, as well as those of a few other commonly occurring herbicides, generally were detected at concentrations similar to or greater than concentrations of the parent compound. Samples typically contained mixtures of two or more compounds. The total number of compounds and their total concentration in samples generally increased with the amount of urban and agricultural land use in a watershed.

    Annual mean concentrations of all compounds were less than human-health benchmarks. Single-sample concentrations of anthropogenic organic compounds in source water generally were less than 0.1 microgram per liter and less than established human-health benchmarks. Human-health benchmarks used for comparison were U.S. Environmental Protection Agency (USEPA) Maximum Contaminant Levels (MCLs) for regulated compounds and U.S. Geological Survey Health-Based Screening Levels for unregulated compounds. About one-half of all detected compounds do not have human-health benchmarks or adequate toxicity information for evaluating results in a human-health context.

    During a second sampling phase (2004–05), source water and finished water (water that has passed through all the treatment processes but prior to distribution) were sampled at eight of the nine community water systems. Water-treatment processes differ among the systems. Specifically, treatment at five of the systems is conventional, typically including steps of coagulation, flocculation, sedimentation, filtration, and disinfection. One water system uses slow sand filtration and disinfection, a second system uses ozone as a preliminary treatment step to conventional treatment, and a third system is a direct filtration treatment plant that uses many of the steps employed in conventional treatment. Most of these treatment steps are not designed specifically to remove the compounds monitored in this study.

    About two-thirds of the compounds detected commonly in source water were detected at similar frequencies in finished water. Although the water-treatment steps differ somewhat among the eight water systems, the amount of change in concentration of the compounds from source- to finished-water samples generally did not differ systematically at one or among the water systems for compounds with similar detection frequencies in source and finished water. Additionally, changes in concentration over time in source water of some compounds, for example seasonal changes in atrazine concentrations, usually were reflected in the associated finished water.

    Some compounds detected in source water were removed or transformed during treatment and, therefore, were not detected in finished water. These included aromatic hydrocarbons with one or more methyl groups, 3,4-dichloroaniline (diuron degradate), the organophosphate insecticides (diazinon and malathion), and fipronil. On the basis of results for matrix spikes, decreases in concentration of these compounds or nondetections in finished water likely were due to degradation or transformation as a result of chlorine disinfection.

    The annual mean concentration of all compounds detected in finished water were less than established human-health benchmarks, and concentrations of most compounds were several orders of magnitude less than human-health benchmarks. With the exception of one detection of atrazine at one site, maximum measured concentrations of all commonly detected compounds in finished water were less than established human-health benchmarks. The annual mean concentration of atrazine at this site was 0.72 microgram per liter, which is less than the MCL of 3 micrograms per liter. Most source- and finished-water samples contained mixtures of 2 or more compounds, and more than one-half of both source- and finished-water samples contained mixtures of 14 or more compounds. Degradates of commonly detected herbicides often were present at a concentration similar to or greater than of that the parent compound in both source and finished water and contributed to the number of compounds detected in mixtures.

    For additional information contact:
    Director, USGS South Dakota Water Science Center
    U.S. Geological Survey
    1608 Mt. View Rd.
    Rapid City, SD 57702
    (605) 394–3200
    World Wide Web: http://sd.water.usgs.gov

    ToxSci Advance Access originally published online on October 21, 2008
    Toxicological Sciences 2009 107(1):56-64; doi:10.1093/toxsci/kfn225
    Published by Oxford University Press 2008.

    The Effects of Triclosan on Puberty and Thyroid Hormones in Male Wistar Rats

    Leah M. Zorrilla*,†, Emily K. Gibson†, Susan C. Jeffay†, Kevin M. Crofton‡, Woodrow R. Setzer§, Ralph L. Cooper† and Tammy E. Stoker†,1

    * Department of Molecular Biomedical Sciences, North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina 27606 † Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development ‡ Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development § National Center for Computational Toxicology, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711

    1 To whom correspondence should be addressed at MD-72, Endocrinology Branch, Reproductive Toxicology Division, NHEERL, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-5138. E-mail: stoker.tammy{at}epa.gov.

    Received August 27, 2008; accepted October 15, 2008

    Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a potentantibacterial and antifungal compound that is widely used inpersonal care products, plastics, and fabrics. Recently triclosanhas been shown to alter endocrine function in a variety of species.The purpose of this study was to determine effects of triclosanon pubertal development and thyroid hormone concentrations inthe male rat. Weanling rats were exposed to 0, 3, 30, 100, 200,or 300 mg/kg of triclosan by oral gavage from postnatal day(PND) 23 to 53. Preputial separation (PPS) was examined beginningon PND 33. Rats were killed on PND 53, organ weights were recordedand serum was collected for subsequent analysis. Triclosan didnot affect growth or the onset of PPS. Serum testosterone wassignificantly decreased at 200 mg/kg, however no effects wereobserved on androgen-dependent reproductive tissue weights.Triclosan significantly decreased total serum thyroxine (T4)in a dose-dependent manner at 30 mg/kg and higher (no observedeffect level of 3 mg/kg). Triiodothyronine (T3) was significantlydecreased only at 200 mg/kg, but thyroid stimulating hormonewas not statistically different at any dose. Liver weights weresignificantly increased at 100 mg/kg triclosan and above suggestingthat the induction of hepatic enzymes may have contributed tothe altered T4 and T3 concentrations, but it does not appearto correlate with the T4 dose-response. This study demonstratesthat triclosan exposure does not alter androgen-dependent tissueweights or onset of PPS; however, triclosan exposure significantlyimpacts thyroid hormone concentrations in the male juvenilerat.

    Key Words: triclosan; puberty; thyroid hormone.

    Disclaimer: The research described in this article has beenreviewed by the National Health and Environmental Effects ResearchLaboratory, U.S. Environmental Protection Agency and approvedfor publication. Approval does not signify that the contentsnecessarily reflect the views and policies of the Agency, nordoes mention of trade names or commercial products constituteendorsement or recommendation for use.

    Online ISSN 1096-0929 - Print ISSN 1096-6080 Copyright © 2008 Society of Toxicology

    Acute Pesticide Poisoning Among Agricultural Workers in the United States, 1998–2005

    Geoffrey M. Calvert, MD, MPH,1* Jennifer Karnik, MPH,1 Louise Mehler, PHD, MD,2 John Beckman, BS,3 Barbara Morrissey, MS,4 Jennifer Sievert, BA,5 Rosanna Barrett, MPH,6 Michelle Lackovic, MPH,7 Laura Mabee, BA,8 Abby Schwartz, MPH,9 Yvette Mitchell, MS,10 and Stephanie Moraga-McHaley, MS11

    Background Approximately 75% of pesticide usage in the United States occurs in agriculture. As such, agricultural workers are at greater risk of pesticide exposure than non-agricultural workers. However, the magnitude, characteristics and trend of acute pesticide poisoning among agricultural workers are unknown.

    Methods We identified acute pesticide poisoning cases in agricultural workers between the ages of 15 and 64 years that occurred from 1998 to 2005. The California Department of Pesticide Regulation and the SENSOR-Pesticides program provided the cases. Acute occupational pesticide poisoning incidence rates (IR) for those employed in agriculture were calculated, as were incidence rate ratios (IRR) among agricultural workers relative to non- agricultural workers.

    Results Of the 3,271 cases included in the analysis, 2,334 (71%) were employed as farmworkers. The remaining cases were employed as processing/packing plant workers (12%), farmers (3%), and other miscellaneous agricultural workers (19%). The majority of cases had low severity illness (N 1/4 2,848, 87%), while 402 (12%) were of medium severity and 20 (0.6%) were of high severity. One case was fatal. Rates of illness among various agricultural worker categories were highly variable but all, except farmers, showed risk for agricultural workers greater than risk for non-agricultural workers by an order of magnitude or more. Also, the rate among female agricultural workers was almost twofold higher compared to males.

    Conclusion The findings from this study suggest that acute pesticide poisoning in the agricultural industry continues to be an important problem. These findings reinforce the need for heightened efforts to better protect farmworkers from pesticide exposure. Am. J. Ind. Med. 51:883–898, 2008. Published 2008 Wiley-Liss, Inc.†

    KEY WORDS: pesticides; surveillance; poisoning; agriculture; farmworkers

    1 Division of Surveillance, Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio

    2 Department of Pesticide Regulation, California Environmental Protection Agency, Sacramento, California

    3 Public Health Institute, Oakland, California

    4 Office of Environmental Assessments,Washington State Department of Health, Olympia, Washington

    5 Environmental and Injury Epidemiology and Toxicology Branch, Texas Department of State Health Services, Austin,Texas

    6 Florida Department of Health,Tallahassee, Florida

    7 Louisiana Department of Health and Hospitals, New Orleans, Louisiana

    8 Office of Environmental Public Health, Oregon Department of Human Services, Portland, Oregon

    9 Division of Environmental Health, Michigan Department of Community Health, Lansing, Michigan

    10 Bureau of Occupational Health, New York State Department of Health,Troy, New York

    11 New Mexico Occupational Health Registry, University of New Mexico, Albuquerque, New Mexico

    The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health or each author's state agency.

    *Correspondence to: Geoffrey M. Calvert, National Institute for Occupational Safety and Health, 4676 Columbia Parkway, R-17, Cincinnati, OH 45226. E-mail: jac6@cdc.gov Accepted 23 June 2008

    DOI 10.1002/ajim.20623. Published online in Wiley InterScience
    (www.interscience.wiley.com)

    Published 2008 Wiley-Liss, Inc.
    †This article is a US Government work and, as such, is in the public domain in the United States of America.

    Click here to read the full article.

    Commonality in Signaling of Endocrine Disruption from Snail to Human

    TAISEN IGUCHI AND YOSHINAO KATSU

    Several nuclear receptors have recently been identified as mediators of endocrine disruption as well as steroid hormone receptors. The ubiquitous environmental contaminant tributyltin chloride (TBT) is a ligand for retinoid X receptor (RXR) in rock shell at the nanomolar level, and it acts as a ligand for both the RXR and the peroxisome proliferator-activated receptor γ in the frog Xenopus laevis and in humans. TBT, which induces imposex in marine snails and promotes adipogenesis in X. laevis and in mice, is an example of an environmental endocrine disrupter that promotes adverse effects, from the snail to mammals, through common signaling. In addition, juvenile hormone agonists used as pesticides showed endocrine- disruptive effects on parthenogenic Daphnia magna, lowering rates of reproduction, and inducing 100% male offspring. In this article, we focus on commonality in signaling through nuclear receptors and newly found endocrine disruption in D. magna.

    Keywords: endocrine-disrupting chemicals, environmental estrogens, organotins, adipogenesis, nuclear receptors

    Click here to read the full article.

    Comment in:
    Ann Neurol. 2008 Jan;63(1):128.

    Pesticide exposure and risk for Parkinson's disease.

    Ascherio A, Chen H, Weisskopf MG, O'Reilly E, McCullough ML, Calle EE, Schwarzschild MA, Thun MJ.

    Department of Nutrition, Harvard School of Public Health, Boston, MA, USA. aascheri@hsph.harvard.edu

    OBJECTIVE: Chronic, low-dose exposure to pesticides is suspected to increase the risk for Parkinson's disease (PD), but data are inconclusive. METHODS: We prospectively examined whether individuals exposed to pesticides have higher risk for PD than those not exposed. The study population comprised participants in the Cancer Prevention Study II Nutrition Cohort, a longitudinal investigation of US men and women initiated in 1992 by the American Cancer Society. Follow-up surveys were conducted in 1997, 1999, and 2001. The 143,325 individuals who returned the 2001 survey and did not have a diagnosis or symptoms of PD at baseline (1992) were included in the analyses. RESULTS: Exposure to pesticides was reported by 7,864 participants (5.7%), including 1,956 farmers, ranchers, or fishermen. Individuals exposed to pesticides had a 70% higher incidence of PD than those not exposed (adjusted relative risk, 1.7; 95% confidence interval, 1.2-2.3; p = 0.002). The relative risk for pesticide exposure was similar in farmers and nonfarmers. No relation was found between risk for PD and exposure to asbestos, chemical/acids/solvents, coal or stone dust, or eight other occupational exposures. INTERPRETATION: These data support the hypothesis that exposure to pesticides may increase risk for PD. Future studies should seek to identify the specific chemicals responsible for this association.

    PMID: 16802290 [PubMed - indexed for MEDLINE]

    Originally published In Press as doi:10.1074/jbc.M802210200 on September 25, 2008

    J. Biol. Chem., Vol. 283, Issue 50, 34696-34703, December 12, 2008

    Ziram Causes Dopaminergic Cell Damage by Inhibiting E1 Ligase of the Proteasome*

    Arthur P. Chou‡, Nigel Maidment§, Rebecka Klintenberg, John E. Casida, Sharon Li‡, Arthur G. Fitzmaurice‡, Pierre-Olivier Fernagut‡||, Farzad Mortazavi‡||, Marie-Francoise Chesselet‡||, and Jeff M. Bronstein‡**1

    From the Departments of ‡Neurology, §Psychiatry, and ||Neurobiology, University of California at Los Angeles David Geffen School of Medicine and the **Greater Los Angeles Veterans Administration Medical Center, Los Angeles, California 90095, and Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, California 94720-3112

    The etiology of Parkinson disease (PD) is unclear but may involve environmental toxins such as pesticides leading to dysfunction of the ubiquitin proteasome system (UPS). Here, we measured the relative toxicity of ziram (a UPS inhibitor) and analogs to dopaminergic neurons and examined the mechanism of cell death. UPS (26 S) activity was measured in cell lines after exposure to ziram and related compounds. Dimethyl- and diethyldithiocarbamates including ziram were potent UPS inhibitors. Primary ventral mesencephalic cultures were exposed to ziram, and cell toxicity was assessed by staining for tyrosine hydroxylase (TH) and NeuN antigen. Ziram caused a preferential damage to TH+ neurons and elevated α-synuclein levels but did not increase aggregate formation. Mechanistically, ziram altered UPS function through interfering with the targeting of substrates by inhibiting ubiquitin E1 ligase. Sodium dimethyldithiocarbamate administered to mice for 2 weeks resulted in persistent motor deficits and a mild reduction in striatal TH staining but no nigral cell loss. These results demonstrate that ziram causes selective dopaminergic cell damage in vitro by inhibiting an important degradative pathway implicated in the etiology of PD. Chronic exposure to widely used dithiocarbamate fungicides may contribute to the development of PD, and elucidation of its mechanism would identify a new potential therapeutic target.

    Received for publication, March 20, 2008, and in revised form, September 24, 2008.

    * This work was supported, in whole or in part, by National Institutes of Health Grant 5 U54 ESO12078. This work was also supported by Veterans Administration Grant SW PADRREC, the National Institutes of Health Medical Scientist Training Program (to A. P. C.), a postdoctoral fellowship from the Swedish Research Council (to R. K.), and funds from the Michael J. Fox Foundation (to F. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    1 To whom correspondence should be addressed: Dept. of Neurology, UCLA School of Medicine, Reed Neurological Research Center, 710 Westwood Plaza, Los Angeles, CA 90095. Fax: 310-206-9819; E-mail: jbronste@ucla.edu

    Full text available from jbc.org.

    Ecological Applications, 18(7), 2008, pp. 1728-1742

    © 2008 by the Ecological Society of America

    AN UNFORESEEN CHAIN OF EVENTS: LETHAL EFFECTS OF PESTICIDES ON FROGS AT SUBLETHAL CONCENTRATIONS

    RICK A. RELYEA1 AND NICOLE DIECKS

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 USA

    Abstract. The field of toxicology has traditionally assessed the risk of contaminants by using laboratory experiments and a range of pesticide concentrations that are held constant for short periods of time (1-4 days). From these experiments, one can estimate the concentration that causes no effect on survival. However, organisms in nature frequently experience multiple applications of pesticides over time rather than a single constant concentration. In addition, organisms are embedded in ecological communities that can propagate indirect effects through a food web. Using outdoor mesocosms, we examined how low concentrations (10-250 lg/L) of a globally common insecticide (malathion) applied at various amounts, times, and frequencies affected aquatic communities containing zooplankton, phytoplankton, periphyton, and larval amphibians (reared at two densities) for 79 days. All application regimes caused a decline in zooplankton, which initiated a trophic cascade in which there was a bloom in phytoplankton and, in several treatments, a subsequent decline in the competing periphyton. The reduced periphyton had little effect on wood frogs (Rana sylvatica), which have a short time to metamorphosis. However, leopard frogs (Rana pipiens) have a longer time to metamorphosis, and they experienced large reductions in growth and development, which led to subsequent mortality as the environment dried. Hence, malathion (which rapidly breaks down) did not directly kill amphibians, but initiated a trophic cascade that indirectly resulted in substantial amphibian mortality. Importantly, repeated applications of the lowest concentration ( a R'R'press treatmentR^R^ consisting of seven weekly applications of 10 lg/L) caused larger impacts on many of the response variables than single R'R'pulseR^R^ applications that were 25 times as great in concentration. These results are not only important because malathion is the most commonly applied insecticide and is found in wetlands, but also because the mechanism underlying the trophic cascade is common to a wide range of insecticides, offering the possibility of general predictions for the way in which many insecticides impact aquatic communities and the populations of larval amphibians.

    Key words: acetylcholine esterase inhibitor; amphibian decline; ecotoxicology; leopard frog (Rana pipiens); pesticide pulse; wood frog (Rana sylvatica).

    Occupational Exposure to Pesticides and Risk of Adult Brain Tumors

    Claudine M. Samanic1, Anneclaire J. De Roos2, Patricia A. Stewart1, Preetha Rajaraman1, Martha A. Waters3 and Peter D. Inskip1

    1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
    2 Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA
    3 National Institute for Occupational Safety and Health, Cincinnati, OH

    Correspondence to Claudine M. Samanic, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Room 8003, Rockville, MD 20852 (e-mail: samanicc{at}mail.nih.gov

    The authors examined incident glioma and meningioma risk associated with occupational exposure to insecticides and herbicides in a hospital-based, case-control study of brain cancer. Cases were 462 glioma and 195 meningioma patients diagnosed between 1994 and 1998 in three US hospitals. Controls were 765 patients admitted to the same hospitals for nonmalignant conditions. Occupational histories were collected during personal interviews. Exposure to pesticides was estimated by use of a questionnaire, combined with pesticide measurement data abstracted from published sources. Using logistic regression models, the authors found no association between insecticide and herbicide exposures and risk for glioma and meningioma. There was no association between glioma and exposure to insecticides or herbicides, in men or women. Women who reported ever using herbicides had a significantly increased risk for meningioma compared with women who never used herbicides (odds ratio = 2.4, 95% confidence interval: 1.4, 4.3), and there were significant trends of increasing risk with increasing years of herbicide exposure (p = 0.01) and increasing cumulative exposure (p = 0.01). There was no association between meningioma and herbicide or insecticide exposure among men. These findings highlight the need to go beyond job title to elucidate potential carcinogenic exposures within different occupations.

    central nervous system neoplasms; incidence; pesticides; United States

    Click here for the full article.

    Pesticide exposure as risk factor for non-Hodgkin lymphoma including histopathological subgroup analysis

    International Journal of Cancer

    Volume 123 Issue 7, Pages 1657 - 1663

    Published Online: 11 Jul 2008

    Copyright © 2008 Wiley-Liss, Inc., A Wiley Company

    Mikael Eriksson 1 *, Lennart Hardell 2, Michael Carlberg 2, Måns Åkerman 3

    1Department of Oncology, University Hospital, Lund, Sweden
    2Department of Oncology, University Hospital, Örebro, Sweden
    3Department of Pathology, University Hospital, Lund, Sweden

    email: Mikael Eriksson (mikael.eriksson@med.lu.se)

    *Correspondence to Mikael Eriksson, Department of Oncology, University Hospital, SE-221 85 Lund, Sweden

    Funded by:
    • FAS; Grant Number: 2001-0224
    • Cancer-och Allergifonden
    • Nyckelfonden
    • Örebro University Hospital Cancer Fund

    Keywords

    phenoxyacetic acids • MCPA • glyphosate • insecticides • impreganting agents • non-Hodgkin lymphoma

    Abstract

    We report a population based case-control study of exposure to pesticides as risk factor for non-Hodgkin lymphoma (NHL). Male and female subjects aged 18-74 years living in Sweden were included during December 1, 1999, to April 30, 2002. Controls were selected from the national population registry. Exposure to different agents was assessed by questionnaire. In total 910 (91 %) cases and 1016 (92%) controls participated. Exposure to herbicides gave odds ratio (OR) 1.72, 95% confidence interval (CI) 1.18-2.51. Regarding phenoxyacetic acids highest risk was calculated for MCPA; OR 2.81, 95% CI 1.27-6.22, all these cases had a latency period >10 years. Exposure to glyphosate gave OR 2.02, 95% CI 1.10-3.71 and with >10 years latency period OR 2.26, 95% CI 1.16-4.40. Insecticides overall gave OR 1.28, 95% CI 0.96-1.72 and impregnating agents OR 1.57, 95% CI 1.07-2.30. Results are also presented for different entities of NHL. In conclusion our study confirmed an association between exposure to phenoxyacetic acids and NHL and the association with glyphosate was considerably strengthened. © 2008 Wiley-Liss, Inc.

    Received: 4 November 2007; Accepted: 20 February 2008

    Digital Object Identifier (DOI)
    10.1002/ijc.23589  About DOI

    Front Biosci. 2008 Jan 1;13:1240-9. Links

    Neurotoxicity of pesticides: a brief review.

    Costa LG, Giordano G, Guizzetti M, Vitalone A.

    Dept. of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA. lgcosta@u.washington.edu

    Pesticides are substances widely used to control unwanted pests such as insects, weeds, fungi and rodents. Most pesticides are not highly selective, and are also toxic to nontarget species, including humans. A number of pesticides can cause neurotoxicity. Insecticides, which kill insects by targeting their nervous system, have neurotoxic effect in mammals as well. This family of chemicals comprises the organophosphates, the carbamates, the pyrethroids, the organochlorines, and other compounds. Insecticides interfere with chemical neurotransmission or ion channels, and usually cause reversible neurotoxic effects, that could nevertheless be lethal. Some herbicides and fungicides have also been shown to possess neurotoxic properties. The effects of pesticides on the nervous system may be involved in their acute toxicity, as in case of most insecticides, or may contribute to chronic neurodegenerative disorders, most notably Parkinson's disease. This brief review highlights some of the main neurotoxic pesticides, their effects, and mechanisms of action.

    PMID: 17981626 [PubMed - indexed for MEDLINE]

    Related ArticlesMechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. [Toxicology. 2002] Risk assessment of neurotoxic pesticides. [Acta Physiol Hung. 2000] Effects of pyrethroids on voltage-sensitive calcium channels: a critical evaluation of strengths, weaknesses, data needs, and relationship to assessment of cumulative neurotoxicity. [Toxicol Appl Pharmacol. 2004] Microbiological and biotechnological aspects of metabolism of carbamates and organophosphates. [Crit Rev Biotechnol. 1992] Pesticides and the soil fauna.

    Agriculture Alters Gonadal Form and Function in the Toad Bufo marinus

    Krista A. McCoy,1,2 Lauriel J. Bortnick,2 Chelsey M. Campbell,2 Heather J. Hamlin,2 Louis J. Guillette Jr.,1,2and Colette M. St. Mary1,2

    1School of Natural Resources and Environment, and 2Department of Zoology, University of Florida, Gainesville, Florida, USA

    BACKGROUND: Many agricultural contaminants disrupt endocrine systems of wildlife. However,evidence of endocrine disruption in wild amphibians living in agricultural areas has been controversial. Typically, studies on the effects of pollutants on wildlife attempt to compare polluted withunpolluted sites.

    OBJECTIVES: We took a novel approach to address this question by explicitly quantifying the rela-tionship between gonadal abnormalities and habitats characterized by differing degrees of agricultural activity.

    METHODS: We quantified the occurrence of gonadal abnormalities and measures of gonadal func-tion in at least 20 giant toads ( Bufo marinus) from each of five sites that occur along a gradient of increasing agricultural land use from 0 to 97%.

    RESULTS: The number of abnormalities and frequency of intersex gonads increased with agriculturein a dose-dependent fashion. These gonadal abnormalities were associated with altered gonadal function. Testosterone, but not 17 ß-estradiol, concentrations were altered and secondary sexualtraits were either feminized (increased skin mottling) or demasculinized (reduced forearm width and nuptial pad number) in intersex toads. Based on the end points we examined, female morphol-ogy and physiology did not differ across sites. However, males from agricultural areas had hormone concentrations and secondary sexual traits that were intermediate between intersex toads and non-agricultural male toads. Skin coloration at the most agricultural site was not sexually dimorphic; males had female coloration.

    CONCLUSIONS: Steroid hormone concentrations and secondary sexual traits correlate with repro-ductive activity and success, so affected toads likely have reduced reproductive success. These reproductive abnormalities could certainly contribute to amphibian population declines occurring inareas exposed to agricultural contaminants.

    KEY WORDS: amphibians, endocrine disruption, intersex, pesticides, secondary sexual traits.Environ Health Perspect 116:1526-1532 (2008). doi:10.1289/ehp.11536 available via http://dx.doi.org/ [Online 3 July 2008]

    Click here to read the full article.

    Prenatal Organochlorine Exposure and Measures of Behavior in Infancy Using the Neonatal Behavioral Assessment Scale (NBAS)

    Sharon K. Sagiv,1 J. Kevin Nugent,2,3 T. Berry Brazelton,2 Anna L. Choi,1 Paige E. Tolbert,4 Larisa M. Altshul,1 and Susan A. Korrick 1,5

    BACKGROUND: Previous literature suggests an association between organochlorines and behavioral measures in childhood, including inattention. OBJECTIVE: This study was designed to assess whether prenatal organochlorine exposure is associated with measures of attention in early infancy.

    METHODS: We investigated an association between cord serum polychlorinated biphenyls (PCBs) and p,p´-dichlorodiphenyl dichloroethene (DDE) levels and measures of attention from the Neonatal Behavioral Assessment Scale (NBAS) in a cohort of 788 infants born 1993–1998 to mothers residing near a PCB-contaminated harbor and Superfund site in New Bedford, Massachusetts.

    RESULTS: Medians (ranges) for the sum of four prevalent PCB congeners and DDE levels were 0.19 (0.01–4.41) and 0.30 (0–10.29) ng/g serum, respectively. For the 542 subjects with an NBAS exam at 2 weeks, we observed consistent inverse associations between cord serum PCB and DDE levels and NBAS measures of alertness, quality of alert responsiveness, cost of attention, and other potential attention-associated measures including self-quieting and motor maturity. For example, the decrement in quality of alert responsiveness score was –0.51 (95% confidence interval, –0.99 to –0.03) for the highest quartile of exposure to the sum of four prevalent PCB congeners compared with the lowest quartile. We found little evidence for an association with infant orientation, habituation, and regulation of state, assessed as summary cluster measures.

    CONCLUSIONS: Our findings provide evidence for an association between low-level prenatal PCB and DDE exposures and poor attention in early infancy. Further analyses will focus on whether organochlorine-associated decrements in attention and attention-related skills in infancy persist in later childhood.

    KEY WORDS: behavior, infant, organochlorines, p,p´-dichlorodiphenyl dichloroethene (DDE), poly- chlorinated biphenyls (PCBs). Environ Health Perspect 116:666–673 (2008). doi:10.1289/ehp.10553 available via http://dx.doi.org/ [Online 24 January 2008]

    The Herbicide Atrazine Activates Endocrine Gene Networks via Non-Steroidal NR5>A Nuclear Receptors in Fish and Mammalian Cells

    A Nuclear Receptors in Fish and Mammalian Cells

    Miyuki Suzawa1,2, Holly A. Ingraham1,2*

    1 Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America2 Department of Physiology, University of California San Francisco, San Francisco, California, United States of America

    Abstract

    Atrazine
    (ATR) remains a widely used broadleaf herbicide in the United States despite the fact that this s-chlorotriazine has been linked to reproductive abnormalities in fish and amphibians. Here, using zebrafish we report that environmentally relevant ATR concentrations elevated zcyp19a1 expression encoding aromatase (2.2 µg/L), and increased the ratio of female to male fish (22 µg/L). ATR selectively increased zcyp19a1, a known gene target of the nuclear receptor SF-1 (NR5A1), whereas zcyp19a2, which is estrogen responsive, remained unchanged. Remarkably, in mammalian cells ATR functions in a cell-specific manner to upregulate SF-1 targets and other genes critical for steroid synthesis and reproduction, including Cyp19A1, StAR, Cyp11A1, hCG, FSTL3, LHß, INHα, αGSU, and 11ß-HSD2. Our data appear to eliminate the possibility that ATR directly affects SF-1 DNA- or ligand-binding. Instead, we suggest that the stimulatory effects of ATR on the NR5A receptor subfamily (SF-1, LRH-1, and zff1d) are likely mediated by receptor phosphorylation, amplification of cAMP and PI3K signaling, and possibly an increase in the cAMP-responsive cellular kinase SGK-1, which is known to be upregulated in infertile women. Taken together, we propose that this pervasive and persistent environmental chemical alters hormone networks via convergence of NR5A activity and cAMP signaling, to potentially disrupt normal endocrine development and function in lower and higher vertebrates.

    Full study: http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0002117

    INTERNATIONAL MEETING FOR AUTISM RESEARCH

    May 15, 2008;   ORAL 2899

    Household Pesticide Use in Relation to Autism

    . Hertz-Picciotto
    Public Health Sciences and the M.I.N.D. Institute, University of California at Davis, Dept PHS, Davis, CA 95616

    I. N. Pessah
    3 Department of Veterinary Molecular Biosciences, University of California at Davis, M.I.N.D. Institute, One Shields Avenue, Davis, CA 95616

    R. Hansen
    Pediatrics and the M.I.N.D. Institute, University of California at Davis, 2825, 50th Street, Sacramento, CA 95817

    P. Krakowiak
    M.I.N.D. Institute, University of California at Davis, 2825 50th Street, Sacramento, CA 95817

    Abstract
    Background: Pesticides affect a number of targets in the CNS, and cross the placenta. One previous report suggests a link between maternal residential proximity to commercial organochlorine pesticide exposure during early prenatal life and the risk of autism. That study did not evaluate individual exposures to household pesticides.

    Objectives: To examine household pesticide use during the prenatal period or early postnatal period in relation to autism.

    Methods: Participants were from the CHARGE (Childhood Autism Risks from Genetics and the Environment study, a large population-based case-control study in California. Autism spectrum disorders were confirmed using the ADI and ADOS. Mothers were extensively interviewed regarding demographics, lifestyle, and prenatal and early postnatal exposures of the child. Questions addressed use of numerous household products, including insecticides for flies and ants, pet shampoos, and weed control products. Interview data were available for 333 ASD cases and 198 confirmed typically developing controls. Logistic regression models were adjusted for family socioeconomic status. An index exposure period was defined as three months prior to conception through the child's first year of life.

    Results: Mothers of ASD children were twice as likely to report using pet shampoos for fleas or ticks during the index period as compared with control mothers: adjusted Odds Ratio (aOR) = 2.0, 95% Confidence Interval (CI) = [1.2, 3.6]. When examined by trimester, the strongest association was during the second trimester: aOR = 2.6, 95% CI = [1.3, 6.0].

    Conclusions: The higher prevalence of self-reported use of pet shampoos by CHARGE study mothers of children with ASD could be due to reporting bias, although many other products did not show differences. Pyrethrins have largely replaced organophosphates for flea control, but early life exposure to pyrethrins has been shown to compromise the blood-brain barrier in rodents, raising concern about prenatal and early postnatal exposures.

    " … reduction of the cognitive potential of a child is a very tragic thing, and an event which has major costs to society as well as to the individual."

    Carpenter, D., 2006.

    Environmental contaminants and learning and memory.

    International Congress Series 1287: 185– 189

    Abstract.
    A number of environmental contaminants are known to cause a reduction in IQ in children exposed prenatally or early in life. These effects are well documented for exposure to lead, methylmercury, polychlorinated biphenyls (PCBs), and cigarette smoke, all of which can reduce IQ by up to 5–7 IQ points. Similar effects may result from exposure to dioxins and some pesticides. In most or all of these situations there are also behavioral changes as a result of exposure, including shortened attention span and hyperactivity. Recent studies have shown that adverse effects of contaminants such as lead and cigarette smoke on IQ occur at lower levels of exposure than previously thought, and that the dose–response relationship is actually steeper at lower concentrations than what is seen at higher levels. While adults are not as sensitive as children, there is evidence for a rather selective loss of memory function in adults exposed to the same substances. Our group has attempted to determine the mechanisms whereby these effects occur using long-term potentiation (LTP), an electrophysiological measure known to be related to learning and memory, studied in rodent brain slices. We find that lead and PCBs both reduce LTP whether given during gestation and lactation or acutely applied to brain slices of unexposed animals. Surprisingly, these very different contaminants appear to have a similar mechanism of action, that being alteration of the activity of protein kinase C.

    [from body of text]

    … Our studies lead to the somewhat surprising hypothesis that these diverse contaminants may be all acting through a common mechanism, and suggest that a target molecule may be protein kinase C. Certainly, more evidence is needed before this can be considered to be proven. However, reduction of the cognitive potential of a child is a very tragic thing, and an event which has major costs to society as well as to the individual. It is critical to both prevent exposure in the first place but also to understand how these decrements of brain function occur if one hopes to find ways to reduce and prevent the harm.

    Roman, G., 2007.

    Autism: Transient in utero hypothyroxinemia related to maternal flavonoid ingestion during pregnancy and to other environmental antithyroid agents.

    Journal of the Neurological Sciences 262 :15–26

    Abstract
    The incidence and prevalence of autism have increased during the past two decades. Despite comprehensive genetic studies the cause of autism remains unknown. This review emphasizes the potential importance of environmental factors in its causation. Alterations of cortical neuronal migration and cerebellar Purkinje cells have been observed in autism. Neuronal migration, via reelin regulation, requires triiodothyronine (T3) produced by deiodination of thyroxine (T4) by fetal brain deiodinases. Experimental animal models have shown that transient intrauterine deficits of thyroid hormones (as brief as 3 days) result in permanent alterations of cerebral cortical architecture reminiscent of those observed in brains of patients with autism. I postulate that early maternal hypothyroxinemia resulting in low T3 in the fetal brain during the period of neuronal cell migration (weeks 8–12 of pregnancy) may produce morphological brain changes leading to autism. Insufficient dietary iodine intake and a number of environmental antithyroid and goitrogenic agents can affect maternal thyroid function during pregnancy. The most common causes could include inhibition of deiodinases D2 or D3 from maternal ingestion of dietary flavonoids or from antithyroid environmental contaminants. Some plant isoflavonoids have profound effects on thyroid hormones and on the hypothalamus–pituitary axis. Genistein and daidzein from soy (Glycine max) inhibit thyroperoxidase that catalyzes iodination and thyroid hormone biosynthesis. Other plants with hypothyroid effects include pearl millet (Pennisetum glaucum) and fonio millet (Digitaria exilis); thiocyanate is found in Brassicae plants including cabbage, cauliflower, kale, rutabaga, and kohlrabi, as well as in tropical plants such as cassava, lima beans, linseed, bamboo shoots, and sweet potatoes. Tobacco smoke is also a source of thiocyanate. Environmental contaminants interfere with thyroid function including 60% of all herbicides, in particular 2,4-dichlorophenoxyacetic acid (2,4-D), acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, mancozeb, and thioureas. Other antithyroid agents include polychlorinated biphenyls (PCBs), perchlorates, mercury, and coal derivatives such as resorcinol, phthalates, and anthracenes. A leading ecological study in Texas has correlated higher rates of autism in school districts affected by large environmental releases of mercury from industrial sources. Mercury is a well known antithyroid substance causing inhibition of deiodinases and thyroid peroxidase. The current surge of autism could be related to transient maternal hypothyroxinemia resulting from dietary and/or environmental exposure to antithyroid agents. Additional multidisciplinary epidemiological studies will be required to confirm this environmental hypothesis of autism.

    Environmental chemicals with antithyroid effects Howdeshell [103] and Colborn [104,105] have recently reviewed the potential effects of environmental chemical agents on endocrine function—causing in particularly thyroid disruption and abnormal brain development. Low doses of toxins could become deleterious in cases of low maternal iodine [104] . Table 2 [103] provides a comprehensive list of chemical agents with effects at several levels of thyroid metabolism. More than 60% of herbicides are endocrine disruptors [104] in particular the widely used 2,4-dichlorophenoxyacetic acid (2,4-D), mancozeb, acetochlor, aminotriazole, amitrole, bromoxynil, pendamethalin, and the thioureas. Contamination of drinking water from areas rich in coal and shale by naturally occurring powerful antithyroid products such as resorcinol (1,3-dihydroxybenzene dihydroxybenzene) and the substituted resorcinol 2,4- dihydroxyacetophenone, methoxy-anthracene, phthalate esters and phthalic acid, can produce endemic goiter and hypothyroidism [106]. The developmental neurotoxicity of polychlorinated biphenyls (PCBs) and dioxins has been known since the 1990s [107,108] . Neurobehavioral alterations have been observed in newborn children exposed to PCBs including motor immaturity, hyporreflexia, and lower psychomotor scores between 6 months and 2 years of age; along with decrease in dopamine in basal ganglia and prefrontal cortex [107] . Similar dopamine alterations have been reported in children with autism [109] . These abnormalities could be mediated by disruptionof thyroid hormones by competitive binding of PCBs (structurally similar to thyroid hormones) to serum transport proteins [110] and by alterations in thyroid hormone-responsive genes in the developing brain [103–105,110–112] . Recently, Kimura-Kuroda et al. [113] demonstrated that several hydroxy- PCBs are capable of inhibiting the thyroid-hormone-dependent development of dendrites in cerebellar Purkinje cells and suggested that PCBs could be a cause of autism and other developmental disorders.

    Although many authors have suggested that environmental pollutants–such as those affecting thyroid hormones– may play a role in autism [85,103–105,112,113,125] only recently Palmer and colleagues [126] , from the University of Texas at San Antonio, reported an ecological association between autism and environmental mercury pollution. This study was based on quantitative data on mercury released in the Texas environment, provided by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The authors correlated environmentally released mercury (per 1000 lb) with rates of autism in Texas using county (N=254) and school district (N=1184) information by means of a multilevel Poisson regression model adjusted for racial composition, socioeconomic level and urbanicity. They concluded that the risk for autism increased 6.15% per each 100 lb of environmentally released mercury (RR=1.614, 95% CI 1.487–1.752); the highest increase in relative rates of autism in school districts was for urban relative to rural (RR=4.726, 95% CI 3.8–5.9) and for suburban vs. rural districts (RR=2.547, 95% CI 2.1–3.2). Autism accounted for the increase in special education rate whereby each 100 lb of mercury released increased 4.3% the rate of special education students (RR=1.433, 95% CI 1.35–1.52) [126]. This study from our institution is one of the first to demonstrate an association between environmental pollution and autism.

    Reproductive Toxicology 25 (2008) 184-191

    Circulating estradiol in men is inversely related to urinary metabolites of nonpersistent insecticides

    John D. Meeker a , * , Sarena R. Ravi a , Dana B. Barr b , Russ Hauser c , d a Department of Environmental Health Sciences, University of Michigan, School of Public Health, Ann Arbor, MI, United States
    b Centers for Disease and Control and Prevention, Atlanta, GA, United States
    c Department of Environmental Health, Harvard School of Public Health, Boston, MA, United States
    d The Fertility Center, Vincent Memorial Obstetrics and Gynecology Service, Massachusetts General Hospital,

    Boston, MA, United States
    Received 14 August 2007; received in revised form 4 December 2007; accepted 19 December 2007
    Available online 28 December 2007

    Abstract
    Background: Estradiol plays an important role in male reproductive health as a germ cell survival factor. Chlorpyrifos and carbaryl, nonpersistent insecticides to which the general population are commonly exposed, were recently shown to inhibit estradiol metabolism in

    vitro which could lead to altered hormone balance. Methods: Subjects (N= 322) were the male partners in couples presenting to a Massachusetts infertility clinic from years 2000-2003. 3,5,6-Trichloro-2-pyridinol (TCPY),

    the major urinary metabolite of chlorpyrifos and chlorpyrifos-methyl, and 1- and 2-naphthol (1N and 2N), urinary metabolites of carbaryl and naphthalene, were measured in a spot urine sample from each subject. Estradiol, sex hormone binding globulin (SHBG), and prolactin were measured in serum collected from subjects during the same clinic visit. Results: Using multiple linear regression, an interquartile range (IQR) increase in TCPYwas

    associated with a 1.36 pg/mL decline (95% confidence interval =-2.91 to -0.22) in estradiol concentration. When estradiol and TCPY were divided into quintiles, there was a dose- dependent increase in the odds of being in the lowest estradiol quintile with increasing TCPY quintiles. Conclusion: On a population level, these reductions in estradiol levels are of potential

    public health importance because of widespread exposure to TCPY and its parent insecticides.

    Complete inhibition of spontaneous activity in neuronal networks in vitro by deltamethrin and permethrin

    Shafer TJ, Rijal SO, Gross GW.

    Neurotoxicology Division, MD-B105-05, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, United States.

    Neurotoxicology. 2008 Jan 19

    Types I and II pyrethroid insecticides cause temporally distinct decreases in voltage-gated sodium channel (VGSC) inactivation rates that are proposed to underlie their characteristic differences in toxicity signs. How alterations in VGSC channel function give rise to the characteristic differences in signs of pyrethroid intoxication is not completely understood, particularly those changes that occur in functional networks of interconnected neurons. To characterize better pyrethroid actions at the network level, effects of the Type I pyrethroid permethrin (PM) and the Type II pyrethroid deltamethrin (DM) on spontaneous glutamate network-dependent spikes and bursts were investigated in primary cultures of frontal cortex or spinal cord neurons grown on microelectrode arrays (MEAs). Fast GABAergic transmission was blocked by BIC, and concentration-dependent effects of DM (1nM to 5muM) and PM (10nM to 50muM) were examined. Both compounds caused concentration-dependent reductions in the network spike and burst rates. DM was more potent than PM, with IC(50) values of approximately 0.13 and approximately 4muM for inhibition of spike rate in cortical and spinal cord neurons, respectively. Both compounds decreased the percentage of spikes that occurred within a burst and increased the interspike interval within bursts. Onset of effects was rapid, but recovery from total activity loss was not readily achievable. Individual neurons responded heterogeneously; activity of most declined monophasically, but activity in others exhibited biphasic responses with increases followed by decreases in activity. In spinal cord, DM caused a greater number of biphasic responses (29%) than PM (10%). These results demonstrate that both DM and PM inhibit activity of glutamatergic networks, but with different potencies.

    http://www.ncbi.nlm.nih.gov/pubmed/18304643?dopt=AbstractPlus

    PMID: 18304643 [PubMed - as supplied by publisher]

    Pesticides and child neurodevelopment.

    Rosas LG, Eskenazi B.

    University of California at Berkeley, School of Public Health, Center for Children s Environmental Health Research, Berkeley, California, USA.

    PURPOSE OF REVIEW: This review summarizes the recent research on pesticide exposure and child neurobehavioral development with a focus on in-utero exposure to organochlorine and organophosphate pesticides. RECENT FINDINGS: Recent studies on in-utero exposure to the organochlorine pesticide dichlorodiphenyltrichloroethane and its breakdown product, dichlorodiphenyldichloroethene, indicate that exposure is associated with poorer infant (6 months and older) and child neurodevelopment. Yet, the studies differ on the domain of development that is affected. Research on organophosphate pesticide exposure and neurodevelopment is limited but suggests some negative association of exposure and neurodevelopment at certain ages. Two reports agree that increased levels of organophosphate exposure in utero result in greater numbers of abnormal reflexes in neonates and studies in older infants and young children also point to a negative association with development. In young children (2-3 years) two separate studies observed an increase in maternally reported pervasive developmental disorder with increased levels of organophosphate exposure. SUMMARY: Given that the literature suggests a link between organochlorine and in-utero pesticide exposure and impaired child neurodevelopment, clinicians should educate parents about prevention of exposure, especially in populations living in agricultural areas or where household use is common.

    PMID: 18332717 [PubMed - as supplied by publisher]

    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=18332717&itool=iconabstr&itool=pubmed

    Carpenter, D., 2006.

    Environmental contaminants and learning and memory.

    International Congress Series 1287: 185– 189

    Abstract.

    A number of environmental contaminants are known to cause a reduction in IQ in children exposed prenatally or early in life. These effects are well documented for exposure to lead, methylmercury, polychlorinated biphenyls (PCBs), and cigarette smoke, all of which can reduce IQ by up to 5–7 IQ points. Similar effects may result from exposure to dioxins and some pesticides. In most or all of these situations there are also behavioral changes as a result of exposure, including shortened attention span and hyperactivity. Recent studies have shown that adverse effects of contaminants such as lead and cigarette smoke on IQ occur at lower levels of exposure than previously thought, and that the dose–response relationship is actually steeper at lower concentrations than what is seen at higher levels. While adults are not as sensitive as children, there is evidence for a rather selective loss of memory function in adults exposed to the same substances. Our group has attempted to determine the mechanisms whereby these effects occur using long-term potentiation (LTP), an electrophysiological measure known to be related to learning and memory, studied in rodent brain slices. We find that lead and PCBs both reduce LTP whether given during gestation and lactation or acutely applied to brain slices of unexposed animals. Surprisingly, these very different contaminants appear to have a similar mechanism of action, that being alteration of the activity of protein kinase C.

    [from body of text]

    "Our studies lead to the somewhat surprising hypothesis that these diverse contaminants may be all acting through a common mechanism, and suggest that a target molecule may be protein kinase C. Certainly, more evidence is needed before this can be considered to be proven. However, reduction of the cognitive potential of a child is a very tragic thing, and an event which has major costs to society as well as to the individual. It is critical to both prevent exposure in the first place but also to understand how these decrements of brain function occur if one hopes to find ways to reduce and prevent the harm."

    Intersex in Smallmouth Bass Coincident with Population and Agriculture in Potomac Watershed

    Released: 2/7/2008 12:50:58 PM

    Contact Information:
    U.S. Department of the Interior, U.S. Geological Survey
    Office of Communication
    119 National Center
    Reston, VA 20192

    For several years, scientists have been working to determine why so many male smallmouth bass in the Potomac River basin have immature female egg cells in their testes - a form of intersex. They are closer to finding an answer.

    Research by the U.S. Geological Survey (USGS) shows that a high incidence of intersex occurs in the Potomac watershed at sites where farming is most intense and where human population density is highest. The study also shows the greatest prevalence of this form of intersex, known as testicular oocytes (TO), occurs in the spring, just before and during the spawning season.

    These results are published in the current edition of the Journal of Aquatic Animal Health.

    "We collected smallmouth bass from the Shenandoah, the South Branch of the Potomac, and out of the basin for comparison," said USGS scientist Vicki Blazer, who led the study. "The fish from the sites with the highest human population density and the most farming had the highest incidences of intersex," said Blazer. "On the Shenandoah, rates of intersex were highest, ranging from 80-100 percent intersex."

    Out of the Potomac basin, the most densely populated heavily farmed site had bass with a TO rate of 75 percent, where less habited sites had 14-35 percent of male bass with TO. Sites along the South Branch of the Potomac ranged from 47-77 percent; again the higher percents corresponding with increased farming and human population.

    Seasonal comparisons are also striking. In the study, the USGS sampled six sites. At every site sampled, the incidence of male bass with TO was significantly higher during the spring pre-spawn to spawning period, ranging from 69-100 percent, compared to the summer post-spawn period, when it ranged from 25-67 percent.

    The reproductive anomalies in the Potomac's smallmouth bass population are not readily apparent on gross examination of an affected fish -- they were discovered by accident. In 2003, scientists investigating massive fish kills and widespread lesions found many individuals with TO while looking at tissues from the testes of male fish under the microscope.

    A prevalence of intersex is not unique to the Potomac basin, nor is it unique to smallmouth bass. It has been documented in other wild fish populations including spot-tail shiners in the St. Lawrence River, white suckers in Colorado, shovelnose sturgeon in the Mississippi, white perch from the Great Lakes, roach fish in the U.K and Denmark, sharp-tooth catfish in South Africa, three-spine stickleback in Germany, and barbel in Italy. It has also been noted in marine and estuarine fishes in Japan, the UK and the Mediterranean.

    At many of these places, it has been associated with known or suspected endocrine disrupting compounds in wastewater effluent, which are not removed during standard sewage treatment, and in runoff from farming operations. These compounds can include estrogen from birth control pills and hormone replacements, pesticides and fertilizers used on crops, and hormones from livestock operations.

    Scientists are continuing to assess the extent of TO in bass in the Potomac River system. They are examining samples collected at reference sites within and outside of the drainage basin to determine a background prevalence of TO for both smallmouth and largemouth bass, and to identify potential causes. They are also assessing the reproductive and general health of fish at sites with high and low prevalence of TO, and evaluating land use in risk assessment.

    Reporters: The article "Intersex (Testicular Oocytes) in Smallmouth Bass from the Potomac River and Selected Nearby Drainages," is available by email dnoseral@usgs.gov

    Studies of fish health are part of the USGS Chesapeake Bay studies, which provide integrated science for improved understanding and management of the Bay ecosystem. More information about USGS Chesapeake Bay studies, and a soon to be released report "USGS Circular 1316, "Synthesis of USGS Science for the Chesapeake Bay Ecosystem and Implications for Environmental Management," can be found at http://chesapeake.usgs.gov/.

    ASAP Environ. Sci. Technol., ASAP Article, 10.1021/es702304c
    Web Release Date: February 20, 2008

    Copyright © 2008 American Chemical Society

    Bioaccumulation of Pharmaceuticals and Other Anthropogenic Waste Indicators in Earthworms from Agricultural Soil Amended With Biosolid or Swine Manure

    Chad A. Kinney,*† Edward T. Furlong,‡ Dana W. Kolpin,§ Mark R. Burkhardt,‡ Steven D. Zaugg,‡ Stephen L. Werner,‡ Joseph P. Bossio,¤ and Mark J. Benottiþ

    Department of Chemistry, Colorado State University at Pueblo, 2200 Bonforte Blvd, Pueblo, Colorado 81001, National Water Quality Laboratory, U.S. Geological Survey, P.O. Box 25046, Denver Federal Center, Denver, Colorado 80225-0046, U.S Geological Survey, 400 S. Clinton St. Suite 269, Iowa City, Iowa 52240-4105, Department of Chemistry and Biochemistry, Eastern Washington University, Cheney, Washington 99004, and U.S. Geological Survey, 2045 Route 112, Building 4, Coram, New York 11727

    Received for review September 14, 2007

    Revised manuscript received December 21, 2007

    Accepted January 7, 2008

    Abstract:

    Analysis of earthworms offers potential for assessing the transfer of organic anthropogenic waste indicators (AWIs) derived from land-applied biosolid or manure to biota. Earthworms and soil samples were collected from three Midwest agricultural fields to measure the presence and potential for transfer of 77 AWIs from land-applied biosolids and livestock manure to earthworms. The sites consisted of a soybean field with no amendments of human or livestock waste (Site 1), a soybean field amended with biosolids from a municipal wastewater treatment plant (Site 2), and a cornfield amended with swine manure (Site 3). The biosolid applied to Site 2 contained a diverse composition of 28 AWIs, reflecting the presence of human-use compounds. The swine manure contained 12 AWIs, and was dominated by biogenic sterols. Soil and earthworm samples were collected in the spring (about 30 days after soil amendment) and fall (140-155 days after soil amendment) at all field sites. Soils from Site 1 contained 21 AWIs and soil from Sites 2 and 3 contained 19 AWIs. The AWI profiles at Sites 2 and 3 generally reflected the relative composition of AWIs present in waste material applied. There were 20 AWIs detected in earthworms from Site 1 (three compounds exceeding concentrations of 1000 µg/kg), 25 AWIs in earthworms from Site 2 (seven compounds exceeding concentrations of 1000 µg/kg), and 21 AWIs in earthworms from Site 3 (five compounds exceeding concentrations of 1000 µg/kg). A number of compounds that were present in the earthworm tissue were at concentrations less than reporting levels in the corresponding soil samples. The AWIs detected in earthworm tissue from the three field sites included pharmaceuticals, synthetic fragrances, detergent metabolites, polycyclic aromatic hydrocarbons (PAHs), biogenic sterols, disinfectants, and pesticides, reflecting a wide range of physicochemical properties. For those contaminants detected in earthworm tissue and soil, bioaccumulation factors (BAF) ranged from 0.05 (galaxolide) to 27 (triclosan). This study documents that when AWIs are present in source materials that are land applied, such as biosolids and swine manure, AWIs can be transferred to earthworms.

    Organochlorines and risk of non-Hodgkin lymphoma

    John J. Spinelli 1 *†, Carmen H. Ng 1, Jean-Philippe Weber 2, Joseph M. Connors 1, Randy D. Gascoyne 1, Agnes S. Lai 1, Angela R. Brooks-Wilson 1, Nhu D. Le 1, Brian R. Berry 1, Richard P. Gallagher 1 1BC Cancer Agency, Vancouver, British Columbia, Canada
    2Centre de Toxicologie du Québec, Sainte-Foy, Québec
    email: John J. Spinelli (jspinelli@bccrc.ca)

    *Correspondence to John J. Spinelli, BC Cancer Agency, 675 W. 10th Avenue, Vancouver, British Columbia, V5Z 1L3 Canada

    †Fax: +604-675-8180.

    Funded by:
    • Canadian Cancer Society through the National Cancer Institute of Canada
    • Canadian Institutes of Health Research
    • Michael Smith Foundation for Health Research

    Abstract

    Organochlorine chemicals and polychlorinated biphenyls (PCBs) have been suspected as possible risk factors for non-Hodgkin lymphoma (NHL). We investigated PCBs and organochlorine pesticides and risk of NHL in a population-based case-control study in British Columbia, Canada. Congeners of PCBs (including dioxinlike congeners) and pesticides or pesticide metabolites were measured in plasma of 422 pretreatment cases and 460 control subjects. This is so far the largest study to examine organochlorines in plasma to date. Several dioxin-like PCB congeners were associated with increased risk of NHL, including dioxin-like PCB nos. 118 and 156 with odds ratios (OR) for the highest versus lowest quartile between 1.6 and 1.8. Several non-dioxin-like congeners also showed significant associations. The PCB congener with the strongest association was no. 180 with an OR for the highest versus the lowest quartile of 1.83 (95% confidence interval = 1.18-2.84). Six pesticide analytes also showed a significant association with NHL; β-hexachlorocyclohexane, p,p´-DDE, hexachlorobenzene, mirex, oxychlordane and trans-nonachlor. The strongest association was found for oxychlordane, a metabolite of the pesticide chlordane (highest vs. lowest quartile OR = 2.68, 95% confidence interval = 1.69-4.24). Our results provide further evidence that organochlorines contribute to NHL risk. © 2007 Wiley-Liss, Inc.

    American Journal of Respiratory and Critical Care Medicine Vol 177. pp. 11-18, (2008)
    © 2008 American Thoracic Society
    doi: 10.1164/rccm.200706-821OC

    Pesticides and Atopic and Nonatopic Asthma among Farm Women in the Agricultural Health Study

    Jane A. Hoppin1, David M. Umbach2, Stephanie J. London1, Paul K. Henneberger3, Greg J. Kullman3, Michael C. R. Alavanja4 and Dale P. Sandler1

    1 Epidemiology Branch and 2 Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina; 3 Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Department of Health and Human Services, Morgantown, West Virginia; and 4 Occupational Epidemiology Branch, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland

    Correspondence and requests for reprints should be addressed to Jane A. Hoppin, Sc.D., NIEHS Epidemiology Branch, MD A3-05, P.O. Box 12233, Research Triangle Park, NC 27709-2233. E-mail: hoppin1@niehs.nih.gov

    Rationale: Risk factors for asthma among farm women are understudied.

    Objectives: We evaluated pesticide and other occupational exposuresas risk factors for adult-onset asthma.

    Methods: Studying 25,814 farm women in the Agricultural Health Study, we used self-reported history of doctor-diagnosed asthma with or without eczema and/or hay fever to create two case groups: patients with atopic asthma and those with nonatopic asthma.We assessed disease-exposure associations with polytomous logistic regression.

    Measurements and Main Results: At enrollment (1993–1997), 702 women (2.7%) reported a doctor's diagnosis of asthma after age 19 years (282 atopic, 420 nonatopic). Growing up on a farm (61% of all farm women) was protective for atopic asthma (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.43–0.70)and, to a lesser extent, for nonatopic asthma (OR, 0.83; 95%CI,0.68–1.02; P value for difference = 0.008). Pesticideuse was almost exclusively associated with atopic asthma. Anyuse of pesticides on the farm was associated only with atopicasthma (OR, 1.46; 95% CI, 1.14–1.87). This associationwith pesticides was strongest among women who had grown up ona farm. Women who grew up on farms and did not apply pesticideshad the lowest overall risk of atopic asthma (OR, 0.41; 95%CI, 0.27–0.62) compared with women who neither grew upon farms nor applied pesticides. A total of 7 of 16 insecticides,2 of 11 herbicides, and 1 of 4 fungicides were significantlyassociated with atopic asthma; only permethrin use on cropswas associated with nonatopic asthma.

    Conclusions: These findings suggest that pesticides may contributeto atopic asthma, but not nonatopic asthma, among farm women.

    Children's environmental health and the precautionary principle

    Jarosinska, D., Gee, D., 2007. Children's environmental health and the precautionary principle.  International Journal of Hygiene and Environmental Health . Article in Press.

    doi:10.1016/j.ijheh.2007.07.017

    Abstract

    The concept of precaution has a long history in medicine and public health. The modern precautionary principle (PP), originating from environmental debates in Germany in the 1970s, has been included in many international agreements, such as the Treaty on European Union. PP is a public policy tool that justifies actions, which protect human health and the environment in face of uncertain risks. The outcome of the application of PP depends on the level, nature, and distribution of acceptable risks and on the availability of alternatives, and can range from taking no action to banning of substances or the activities of concern.

    Given the complex nature and uncertainty of environmental risks to children's health, a precautionary approach is warranted. Public health professionals and clinical practitioners could adopt such an approach within the wider context of considering the environment as a source of risks to children's health. Relevant knowledge and skills are needed to enable health care professionals to address these issues. New methodological and scientific approaches are necessary to make use of scattered, but potentially relevant clinical evidence in providing ‘early warnings’ of health hazards.

    Multiple exposure to pesticides and impacts on health: a cross- section study of 102 rural workers, Nova Friburgo, Rio de Janeiro State, Brazil

    Araújo AJ, Lima JS, Moreira JC, Jacob SD, Soares MD, Monteiro MC, Amaral AM, Kubota A, Meyer A, Cosenza CA, Neves CD, Markowitz S. NETT, IDT, HUCFF, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-913.

    Cien Saude Colet. 2007 Mar;12(1):115-130.

    A cross section study was carried out in a farming community from Nova Friburgo, Rio de Janeiro state, Brazil, to examine epidemiological, clinical and laboratory aspects of multiple exposure episodes of acute intoxication by organophosphorates either described behavioral syndromes and psychiatric disorders associated to the continued use of pesticides were diagnosed. These results indicate recurrent multiple overexposures to high concentrations of different chemicals, with serious damage to vital functions, especially considering their young age (average 35 &plusmn; 11 years old) and the productive period in their lifetime.

    These results show how important it is to monitor multiple exposure to pesticides - a chain of events that may have major impacts on public health and the environment.

    http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17680063&itool=pubmed_DocSum

    PMID: 17680063 [PubMed - as supplied by publisher]

    Maternal Residence Near Agricultural Pesticide Applications and Autism Spectrum Disorders among Children in the California Central Valley

    Eric M. Roberts,1 Paul B. English,2 Judith K. Grether,2 Gayle C. Windham,2 Lucia Somberg,3 and Craig Wolff2

    1Public Health Institute, Oakland, California, USA; 2California Department of Health Services, Richmond, California, USA; 3School of Public Health, University of California, Berkeley, California, USA

    Abstract
    Background: Ambient levels of pesticides ("pesticide drift") are detectable at residences near agricultural field sites.

    Objective: Our goal was to evaluate the hypothesis that maternal residence near agricultural pesticide applications during key periods of gestation could be associated with the development of autism spectrum disorders (ASD) in children.

    Methods: We identified 465 children with ASD born during 1996–1998 using the California Department of Developmental Services electronic files, and matched them by maternal date of last menstrual period to 6,975 live-born, normal-birth-weight, term infants as controls. We determined proximity to pesticide applications using California Department of Pesticide Regulation records refined using Department of Water Resources land use polygons. A staged analytic design applying a priori criteria to the results of conditional logistic regressions was employed to exclude associations likely due to multiple testing error.

    Results: Of 249 unique hypotheses, four that described organochlorine pesticide applications—specifically those of dicofol and endosulfan—occurring during the period immediately before and concurrent with central nervous system embryogenesis (clinical weeks 1 through 8) met a priori criteria and were unlikely to be a result of multiple testing. Multivariate a posteriori models comparing children of mothers living within 500 m of field sites with the highest nonzero quartile of organochlorine poundage to those with mothers not living near field sites suggested an odds ratio for ASD of 6.1 (95% confidence interval, 2.4–15.3) . ASD risk increased with the poundage of organochlorine applied and decreased with distance from field sites.

    Conclusions: The association between residential proximity to organochlorine pesticide applications during gestation and ASD among children should be further studied.

    The full version of this article is available for free in HTML or PDF formats.

    Zhang, S-Y, Y Ito, O Yamanoshita, Y Yanagiba, M Kobayashi, K Taya, C-M Li, A Okamura, M Miyata, J Ueyama, C-H Lee, M Kamijima and T Nakajima.   Endocrinology, in press.

    This version published online on April 26, 2007
    Endocrinology, doi:10.1210/en.2006-1497
    Submitted on November 13, 2006
    Accepted on April 18, 2007

    Permethrin May Disrupt Testosterone Biosynthesis via Mitochondrial Membrane Damage of Leydig Cells in Adult Male Mouse

    Shu-Yun Zhang, Yuki Ito, Osamu Yamanoshita, Yukie Yanagiba, Miya Kobayashi, Kazuyoshi Taya, Chun-Mei Li, Ai Okamura, Maiko Miyata, Jun Ueyama, Chul-Ho Lee, Michihiro Kamijima, and Tamie Nakajima*

    Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; College of Human life and Environment, Kinjo Gakuin University, Nagoya 463-8521, Japan; Department of Basic Veterinary Science, the United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan; Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan; Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya 461-8673, Japan

    * To whom correspondence should be addressed. E-mail: tnasu23@med.nagoya-u.ac.jp .

    Permethrin, a popular synthetic pyrethroid insecticide used to control noxious insects in agriculture, forestry, households, horticulture and public health throughout the world, poses risks of environmental exposure. Here we evaluate the reproductive toxicity of cis-permethrin in adult male ICR mice that were orally administered cis-permethrin (0, 35 or 70 mg/kg/day) for 6 wk. Caudal epididymal sperm count and sperm motility in the treated groups were statistically reduced in a dose-dependent manner. Testicular testosterone production and plasma testosterone concentration were decreased with an increase in luteinizing hormone (LH) significantly and dose-dependently and a significant regression was observed between testosterone levels and cis-permethrin residues in individual mice testes after exposure. However, no significant changes were observed in body, reproductive organ absolute and relative weights, sperm morphology, and plasma follicle stimulating hormone (FSH) concentration after cis-permethrin treatment. Moreover, cis-permethrin exposure significantly diminished the testicular mitochondrial mRNA expression levels of peripheral benzodiazepine receptor (PBR), steroidogenic acute regulatory protein (StAR), and cytochrome P450 side-chain cleavage (P450scc) enzyme and protein expression levels of StAR and P450scc. At the electron microscopic level, mitochondrial membrane damage was found in Leydig cells of the exposed mouse testis. Our results suggest that insecticide permethrin may cause the mitochondrial membrane impairment in Leydig cells and disrupt testosterone biosynthesis by diminishing the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone in the cells, thus reducing subsequent testosterone production.
    1: Rev Environ Health. 2007 Jan-Mar;22(1):57-73.

    The interrelation between organophosphate toxicity and the epidemiology of depression and suicide.

    Mount Sinai School of Medicine, Department of Psychiatry, New York, NY, USA. Kushik.Jaga@va.gov

    The literature on an association between organophosphate (OP) toxicity and depression or suicide is scarce. An interrelation exists among populations exposed to OPs, acute OP toxicity, neurobehavioral effects, depression, suicide, and fatality. Acute OP toxicity is characterized by the cholinergic syndrome with systemic and central nervous system effects. Organophosphate-induced neurobehavioral effects result in depression. A potential risk of depression and suicide exists in farm workers exposed to OPs. The sociodemographics of depression include age, gender, race, geographic region, social factors, economics, psychiatric disorders, medical conditions, and hereditary factors. Suicide is a major consequence of depression, with multiple sociodemographic risk factors. Developing countries have a higher incidence of OP toxicity, with limited information on the prevalence of depression. In these countries, the incidence of suicide is high, affecting more females. Suicide is more prevalent in rural areas, and in farming communities, commonly with ingestion of OPs. In industrialized countries,=20the incidence of OP toxicity is lower, but the prevalence of depression is higher. Suicide rates are lower in industrialized countries, affecting more males, the urban population, and farming communities. Other lethal methods of suicide, such as hanging, firearms, electrocution, and drug overdose are more common in industrialized countries. A potential risk of depression or suicide certainly exists from OP toxicity, largely depending on the epidemiology or sociodemographics of these disorders. Scientific evidence shows that the association between environmental toxicology and psychiatry has important public health implications.

    PMID: 17508698 [PubMed - in process]




    Atopy, exposure to pesticides and risk of non-Hodgkin lymphoma.

    Vajdic CM, Fritschi L, Grulich AE, Kaldor JM, Benke G, Kricker A, Hughes AM, Turner JJ, Milliken S, Goumas C, Armstrong BK

    National Centre in HIV Epidemiology and Clinical Research, University of NSW, Darlinghurst, NSW, Australia.

    Pesticide exposure has been associated with non-Hodgkin lymphoma (NHL) risk in a number of studies, and two recent studies suggest that the increased risk may be confined to those with a history of asthma. We examined the interaction between occupational pesticide exposure and atopy on risk of NHL in an Australian population-based case-control study. Incident cases (n = 694) were diagnosed in New South Wales or the Australian Capital Territory between 2000 and 2001 and controls (n = 694) were randomly selected from electoral rolls and frequency-matched to cases by age, sex and State of residence. Occupational pesticide exposure was determined by an expert occupational hygienist's assessment of job-specific questionnaires administered by telephone. History of atopy (asthma, hay fever, eczema and food allergy) was self-reported. Logistic regression models included the three matching variables, ethnicity and sun exposure. The OR for NHL with substantial pesticide exposure and any history of asthma was 3.07 (95% CI 0.55-17.10) and with substantial pesticide exposure and no asthma history it was 4.23 (95% CI 1.76-10.16). The p-value for interaction was 0.29. A similar pattern of risk was observed for each of the pesticide subtypes; for asthma at various times of life; for hay fever, eczema, food allergy and any atopy, in men only and for follicular lymphomas only. Although this study had limited power, the findings do not suggest modification of the association between pesticide exposure and NHL risk by asthma or atopic disease more generally. (c) 2007 Wiley-Liss, Inc.

    Increased Rate of Hospitalization for Diabetes and Residential Proximity of Hazardous Waste Sites

    Maria Kouznetsova,1 Xiaoyu Huang,1 Jing Ma,1 Lawrence Lessner,1,2 and David O. Carpenter2

    1Department of Epidemiology and Biostatistics, School of Public Health, and 2Institute for Health and the Environment, University at Albany, Rensselaer, New York, USA

    Full Article in PDF

    Abstract
    Background: Epidemiologic studies suggest that there may be an association between environmental exposure to persistent organic pollutants (POPs) and diabetes.

    Objective: The aim of this study was to test the hypothesis that residential proximity to POP-contaminated waste sites result in increased rates of hospitalization for diabetes.

    Methods: We determined the number of hospitalized patients 25–74 years of age diagnosed with diabetes in New York State exclusive of New York City for the years 1993–2000. Descriptive statistics and negative binomial regression were used to compare diabetes hospitalization rates in individuals who resided in ZIP codes containing or abutting hazardous waste sites containing POPs ("POP" sites); ZIP codes containing hazardous waste sites but with wastes other than POPs ("other" sites); and ZIP codes without any identified hazardous waste sites ("clean" sites).

    Results: Compared with the hospitalization rates for diabetes in clean sites, the rate ratios for diabetes discharges for people residing in POP sites and "other" sites, after adjustment for potential confounders were 1.23 [95% confidence interval (CI), 1.15–1.32] and 1.25 (95% CI, 1.16–1.34), respectively. In a subset of POP sites along the Hudson River, where there is higher income, less smoking, better diet, and more exercise, the rate ratio was 1.36 (95% CI, 1.26–1.47) compared to clean sites.

    Conclusions: After controlling for major confounders, we found a statistically significant increase in the rate of hospitalization for diabetes among the population residing in the ZIP codes containing toxic waste sites.

    Key words: behavior, diabetes mellitus, dioxins, negative binomial regression, PCBs, persistent pesticides, polychlorinated biphenyls, SES, socioeconomic status, ZIP codes. Environ Health Perspect 115:75–79 (2007). [Online 18 August 2006]

    Unidentified inert ingredients in pesticides: implications for human and environmental health.


    Center for Environmental Health, Oakland, California, USA.

    Background: By statute or regulation in the United States and elsewhere, pesticide ingredients are divided into two categories: active and inert (sometimes referred to as other ingredients, adjuvants, or coformulants). Despite their name, inert ingredients may be biologically or chemically active and are labeled inert only because of their function in the formulated product. Most of the tests required to register a pesticide are performed with the active ingredient alone, not the full pesticide formulation. Inert ingredients are generally not identified on product labels and are often claimed to be confidential business information.

     

    Objectives: In this commentary, we describe the shortcomings of the current procedures for assessing the hazards of pesticide formulations and demonstrate that inert ingredients can increase the toxicity of and potential exposure to pesticide formulations.

     

    Discussion: Inert ingredients can increase the ability of pesticide formulations to affect significant toxicologic end points, including developmental neurotoxicity, genotoxicity, and disruption of hormone function. They can also increase exposure by increasing dermal absorption, decreasing the efficacy of protective clothing, and increasing environmental mobility and persistence. Inert ingredients can increase the phytotoxicity of pesticide formulations as well as the toxicity to fish, amphibians, and microorganisms.

     

    Conclusions: Pesticide registration should require full assessment of formulations. Evaluations of pesticides under the National Environmental Policy Act, the Endangered Species Act, and similar statutes should include impact assessment of formulations. Environmental monitoring for pesticides should include inert ingredients. To enable independent research and risk assessment, inert ingredients should be identified on product labels.

    PMID: 17185266
    [PubMed - in process]

    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17185266&itool=iconabstr&itool=pubmed_DocSum

    An Intervention To Reduce Residential Insecticide Exposure During Pregnancy Among An Inner-City Cohort.

    Williams MK, Barr DB, Camann DE, Cruz LA, Carlton EJ, Borjas M, Reyes A, Evans D, Kinney PL, Whitehead RD Jr, Perera FP, Matsoanne S, Whyatt RM.

    Environ Health Perspect. 2006 Nov;114(11):1684-9.

    Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.

    BACKGROUND: We previously reported widespread insecticide exposure during pregnancy among inner-city women from New York City. Here we report on a pilot intervention using integrated pest management (IPM) to reduce pest infestations and residential insecticide exposures among pregnant New York City African-American and Latina women (25 intervention and 27 control homes). METHODS: The IPM consisted of professional cleaning, sealing of pest entry points, application of low-toxicity pesticides, and education. Cockroach infestation levels and 2-week integrated indoor air samples were collected at baseline and one month postintervention. The insecticides detected in the indoor air samples were also measured in maternal and umbilical cord blood collected at delivery. RESULTS: Cockroach infestations decreased significantly (p = 0.016) after the intervention among intervention cases but not control households. Among the intervention group, levels of piperonyl butoxide (a pyrethroid synergist) were significantly lower in indoor air samples after the intervention (p = 0.016). Insecticides were detected in maternal blood samples collected at delivery from controls but not from the intervention group. The difference was significant for trans-permethrin (p = 0.008) and of borderline significance (p = 0.1) for cis-permethrin and 2-isopropoxyphenol (a propoxur metabolite). CONCLUSION: To our knowledge, this is the first study to use biologic dosimeters of prenatal pesticide exposure for assessing effectiveness of IPM. These pilot data suggest that IPM is an effective strategy for reducing pest infestation levels and the internal dose of insecticides during pregnancy.

    Link to PDF

    Pesticide measurements from the first national environmental health survey of child care centers using a multi-residue GC/MS analysis method.

    Tulve NS, Jones PA, Nishioka MG, Fortmann RC, Croghan CW, Zhou JY, Fraser A, Cavel C, Friedman W.

    National Exposure Research Laboratory, U.S. Environmental Protection Agency, MD-E20504, Research Triangle Park, North Carolina 27709, USA. tulve.nicolle@epa.gov

    The U.S. Department of Housing and Urban Development, in collaboration with the U.S. Consumer Product Safety Commission and the U.S. Environmental Protection Agency, characterized the environments of young children (<6 years) by measuring lead, allergens, and pesticides in a randomly selected nationally representative sample of licensed institutional child care centers. Multi-stage sampling with clustering was used to select 168 child care centers in 30 primary sampling units in the United States. Centers were recruited into the study by telephone interviewers. Samples for pesticides, lead, and allergens were collected at multiple locations in each center by field technicians. Field sampling was conducted from July through October 2001. Wipe samples from indoor surfaces (floors, tabletops, desks) and soil samples were collected at the centers and analyzed using a multi-residue GC/MS analysis method. Based on the questionnaire responses, pyrethroids were the most commonly used pesticides among centers applying pesticides. Among the 63% of centers reporting pesticide applications, the number of pesticides used in each center ranged from 1 to 10 and the frequency of use ranged from 1 to 107 times annually. Numerous organophosphate and pyrethroid pesticides were detected in the indoor floor wipe samples. Chlorpyrifos (0.004-28 ng/cm2), diazinon (0.002-18 ng/cm2), cis-permethrin (0.004-3 ng/cm2), and

    PMID: 17120552 [PubMed - in process]

    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17120552&itool=iconabstr&itool=pubmed_DocSum
    Published online November 20, 2006 PEDIATRICS (doi:10.1542/peds.2006-0338)

    ARTICLE

    Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First 3 Years of Life Among Inner-City Children


     Virginia A. Rauh, ScDa, Robin Garfinkel, PhDa, Frederica P. Perera, DrPHa, Howard F. Andrews, PhDa, Lori Hoepner, MPHa, Dana B. Barr, PhD, DLSb, Ralph Whitehead, MPHb, Deliang Tang, DrPHa and Robin W. Whyatt, DrPHa
    a Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, New York
    b National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia
    OBJECTIVE.: The purpose of this study was to investigate the impact of prenatal exposure to chlorpyrifos on 3-year neurodevelopment and behavior in a sample of inner-city minority children.
    METHODS.: As part of an ongoing prospective cohort study in an inner-city minority population, neurotoxicant effects of prenatal exposure to chlorpyrifos were evaluated in 254 children through the first 3 years of life. This report examined cognitive and motor development at 12, 24, and 36 months (measured with the Bayley Scales of Infant Development II) and child behavior at 36 months (measured with the Child Behavior Checklist) as a function of chlorpyrifos levels in umbilical cord plasma.
    RESULTS.: Highly exposed children (chlorpyrifos levels of >6.17 pg/g plasma) scored, on average, 6.5 points lower on the Bayley Psychomotor Development Index and 3.3 points lower on the Bayley Mental Development Index at 3 years of age compared with those with lower levels of exposure. Children exposed to higher, compared with lower, chlorpyrifos levels were also significantly more likely to experience Psychomotor Development Index and Mental Development Index delays, attention problems, attention-deficit/hyperactivity disorder problems, and pervasive developmental disorder problems at 3 years of age.
    CONCLUSIONS.: The adjusted mean 36-month Psychomotor Development Index and Mental Development Index scores of the highly and lower exposed groups differed by only 7.1 and 3.0 points, respectively, but the proportion of delayed children in the high-exposure group, compared with the low-exposure group, was 5 times greater for the Psychomotor Development Index and 2.4 times greater for the Mental Development Index, increasing the number of children possibly needing early intervention services.

    Key Words: pesticides * chlorpyrifos * neurodevelopment * behavior problems
    Abbreviations:
    ADHD-attention-deficit/hyperactivity disorder * BSID-II-Bayley Scales of Infant Development II * CBCL-Child Behavior Checklist * DSM-IV-Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition * EPA-Environmental Protection Agency * ETS-environmental tobacco smoke * HOME-Home Observation for Measurement of the Environment * MDI-Mental Development Index * PDD-pervasive developmental disorder * PDI-Psychomotor Development Index * GLM-general linear modeling * CI-confidence interval
    Prenatal exposure to the pesticide chlorpyrifos is associated with developmental delays in children and attention deficit hyperactivity problems. The proportion of New York City 3-yr olds showing delayed development was five times greater in the higher exposure group. Pediatrics.

    http://pediatrics.aappublications.org/cgi/content/abstract/peds.2006-0338v1?papetoc

    The bactericidal agent triclosan modulates thyroid hormone-associated gene expression and disrupts postembryonic anuran development

    Nik Veldhoena, Rachel C. Skirrowb, Heather Osachoffb, Heidi Wigmoreb, David J. Clapsona, Mark P. Gundersona, Graham Van Aggelenb and Caren C. Helbinga, Corresponding Author Contact Information, E-mail The Corresponding Author

    aDepartment of Biochemistry and Microbiology, P.O. Box 3055, Stn. CSC, University of Victoria, Victoria, British Columbia V8W 3P6, Canada

    bPacific Environmental Science Centre, 2645 Dollarton Highway, North Vancouver, British Columbia V7H 1V2, Canada

    Received 26 July 2006; revised 17 August 2006; accepted 30 August 2006. Available online 29 September 2006.

    Abstract

    We investigated whether exposure to environmentally relevant concentrations of the bactericidal agent, triclosan, induces changes in the thyroid hormone-mediated process of metamorphosis of the North American bullfrog, Rana catesbeiana and alters the expression profile of thyroid hormone receptor (TR) α and β, basic transcription element binding protein (BTEB) and proliferating nuclear cell antigen (PCNA) gene transcripts. Premetamorphic tadpoles were immersed in environmentally relevant concentrations of triclosan and injected with 1 × 10-11 mol/g body weight 3,5,3´-triiodothyronine (T3) or vehicle control. Morphometric measurements and steady-state mRNA levels obtained by quantitative polymerase chain reaction were determined. mRNA abundance was also examined in Xenopus laevis XTC-2 cells treated with triclosan and/or 10 nM T3. Tadpoles pretreated with triclosan concentrations as low as 0.15 ± 0.03 μg/L for 4 days showed increased hindlimb development and a decrease in total body weight following T3 administration. Triclosan exposure also resulted in decreased T3-mediated TRβ mRNA expression in the tadpole tail fin and increased levels of PCNA transcript in the brain within 48 h of T3 treatment whereas TRα and BTEB were unaffected. Triclosan alone altered thyroid hormone receptor α transcript levels in the brain of premetamorphic tadpoles and induced a transient weight loss. In XTC-2 cells, exposure to T3 plus nominal concentrations of triclosan as low as 0.03 μg/L for 24 h resulted in altered thyroid hormone receptor mRNA expression. Exposure to low levels of triclosan disrupts thyroid hormone-associated gene expression and can alter the rate of thyroid hormone-mediated postembryonic anuran development.

    Keywords: Thyroid hormone; Metamorphosis; Rana catesbeiana; XTC-2; Environmental contaminant; Triclosan; Endocrine disruptor; Irgasan

    Behavioral and neurochemical effects induced by pyrethroid-based mosquito repellent exposure in rat offsprings during prenatal and early postnatal period

    Chaitali Sinhaa, Kavita Setha, Fakhrul Islamb, Rajnish Kumar Chaturvedia, Shubha Shuklaa, Neeraj Mathurc, N. Srivastavaa and Ashok Kumar Agrawala, Contact, email

    aDevelopmental Toxicology Division, Industrial Toxicology Research Centre, Post Box-80, M.G. Marg Lucknow 226001, India
    bDepartment of Toxicology, Jamia Hamdard (Hamdard University), New Delhi 110062, India
    cEpidemiology Division, Industrial Toxicology Research Centre, Post Box-80, M.G. Marg Lucknow 226001, India

    Received 5 April 2005;  revised 20 February 2006;  accepted 28 March 2006.  Available online 13 July 2006.


    Abstract

    Synthetic pyrethroids, besides their use in agriculture, are prevalently used in our houses as mosquito repellent (MR) in the form of aerosol, mats, coils and liquid vaporizers. Inhalation of fumes of the MR/liquid vaporizers may get entry into the brain by breaching the developing blood–brain barrier, hence deleterious to developing nervous system and can lead to long-term functional deficits. In the present study the consequence of MR exposure has further been investigated at various stages of development, evaluating free radical mediated effect pertinent to neurobehavioral and neurochemical functioning. Rat pups were exposed to pyrethroid-based MR (allethrin 3.6% w/v, 8 h/day through inhalation) during prenatal (GD1–20), postnatal (PND1–30) and perinatal (GD1–PND30) period of development and assessments were made on PND31. We observed significant oxidative stress, where an increase in lipid peroxidation and a decrease in antioxidants, glutathione, superoxide dismutase and catalase in various brain areas (cerebellum, corpus striatum, frontal cortex and hippocampus) were evident at all the exposure schedules. The hippocampus was the most affected region and further exhibited altered cholinergic functioning in the form of significant decrease in cholinergic (muscarinic) receptor binding (prenatal 32%, postnatal 35%, perinatal 38%) and inhibition in acetylcholinesterase activity (prenatal 20%, postnatal 31% and perinatal 33%). The neurochemical changes were found to accompany decrease in learning and memory performance in exposed rats, the function governed by hippocampus. The result suggests that pyrethroid-based MR inhalation during early developmental period may have adverse effect on developing nervous system causing cholinergic dysfunction leading to learning and memory deficit.

    Keywords: Pyrethroid; Mosquito repellent; Oxidative stress; Hippocampus; Cholinergic (muscarinic) receptor; Learning and memory; Acetylcholinesterase; Development; Rats


    Corresponding author. Tel.: +91 522 2620207; fax: +91 522 2628227.
    Volume 28, Issue 4 , July-August 2006, Pages 472-481

    Environmental Health Perspectives Volume 114, Number 9, September 2006 Research | Children's Health

    A Longitudinal Approach to Assessing Urban and Suburban Children's Exposure to Pyrethroid Pesticides

    Chensheng Lu,1 Dana B. Barr,2 Melanie Pearson,1 Scott Bartell,1 and Roberto Bravo

    1Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA; 2National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA

    Abstract

    We conducted a longitudinal study to assess the exposure of 23 elementary school–age children to pyrethroid pesticides, using urinary pyrethroid metabolites as exposure biomarkers. We substituted most of the children's conventional diets with organic food items for 5 consecutive days and collected two daily spot urine samples, first morning and before bedtime voids, throughout the 15-day study period. We analyzed urine samples for five common pyrethroid metabolites. We found an association between the parents' self-reported pyrethroid use in the residential environment and elevated pyrethroid metabolite levels found in their children's urine. Children were also exposed to pyrethroids through their conventional diets, although the magnitude was smaller than for the residential exposure. Children's ages appear to be significantly associated with pyrethroids exposure, which is likely attributed to the use of pyrethroids around the premises or in the facilities where older children engaged in the outdoor activities. We conclude that residential pesticide use represents the most important risk factor for children's exposure to pyrethroid insecticides. Because of the wide use of pyrethroids in the United States, the findings of this study are important for both children's pesticide exposure assessment and environmental public health. Key words: children's pesticide exposure, dietary exposure, PBA, permethrin, pyrethroids, residential exposure, trans-DCCA, urinary biomarker. Environ Health Perspect 114: 1419–1423 (2006) . doi:10.1289/ehp.9043 available via http://dx.doi.org/ [Online 26 April 2006]

    Address correspondence to C. Lu, 1518 Clifton Rd. NE, Atlanta, GA 30322 USA. Telephone: (404) 727-2131. Fax: (404) 727-8744. E-mail: clu2@sph.emory.edu

    We express our sincere appreciation to the children who participated and to their parents who greatly assisted in this study. We also thank R. Irish, K. Toepel, and P. Sande for their assistance in conducting this study, and A. Bishop, P. Restrepo, R. Walker, J. Nguyen, and D. Walden at the National Center for Environmental Health (NCEH) in the Centers for Disease Control and Prevention (CDC) for their help with sample analysis.

    This study was supported by the U.S. Environmental Protection Agency (EPA) , Science to Achieve Results (STAR) program (RD-829364) , and the NCEH, CDC. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the U.S. EPA or CDC.

    The authors declare they have no competing financial interests.

    Received 26 January 2006 ; accepted 26 April 2006.

    Review and meta-analysis of risk estimates for prostate cancer in pesticide manufacturing workers

    Cancer Causes and Controls, 2006 May;17(4):353-73.


    Van Maele-Fabry G, Libotte V, Willems J, Lison D.

    Unite de Toxicologie Industrielle et Medecine du travail, Ecole de Sante Publique, Universite Catholique de Louvain, Bruxelles, Belgium.


    PURPOSE: The purpose of the present paper is to review cohort studies that examined the occurrence of prostate cancer in pesticide manufacturing workers in order to undertake a qualitative and quantitative evaluation of the risk as well as to assess the level of epidemiological evidence for each class of chemical compounds. METHODS: Following a systematic literature search, relative risk (RR) estimates for prostate cancer were extracted from 18 studies published between 1984 and 2004. All studies were summarised and evaluated for homogeneity and publication bias. As no significant heterogeneity was detected, combined RR estimators were calculated using a fixed effect model. Meta-analyses were performed both on the whole set of data and for each chemical class separately. RESULTS: The meta-rate ratio estimate for all studies was 1.28 [95% confidence interval (CI) 1.05-1.58]. After stratification by specific chemical class, consistent increases in the risk of prostate cancer were found in all groups but statistical significance was found only for accidental or non-accidental exposure to phenoxy herbicides contaminated with dioxins and furans. There was no obvious indication of publication bias. CONCLUSION: The overall meta-analysis provides additional quantitative evidence consistent with prior reviews focusing on other groups exposed to pesticides (farmers, pesticide applicators). The results again point to occupational exposure to pesticides as a possible risk factor for prostate cancer but the question of causality remains unanswered. Epidemiological evidence did not allow identifying a specific pesticide or chemical class that would be responsible for the increased risk but the strongest evidence comes from workers exposed to phenoxy herbicides possibly in relation with dioxin and/or furan contamination.

     Neurology. 2006 Jul 5; [Epub ahead of print] Related Articles,

    Paraoxonase cluster polymorphisms are associated with sporadic ALS.

    Saeed M, Siddique N, Hung WY, Usacheva E, Liu E, Sufit RL, Heller SL, Haines JL, Pericak-Vance M, Siddique T.

    From the Davee Department of Neurology and Clinical Neurosciences (M.S., N.S., W.-Y.H., E.U., E.L., R.L.S., S.L.H.), Feinberg School of Medicine, Northwestern University, Chicago, IL; Center for Human Genetics Research (J.L.H.), Vanderbilt University Medical Center, Nashville, TN; Center for Human Genetics (M.P.-V.), Duke University Medical Center, Durham, NC; and Department of Cell and Molecular Biology (T.S.), Northwestern University Institute of Neuroscience, Chicago, IL.

    Abstract-- BACKGROUND: Paraoxonases (PONs) are involved in the detoxification of organophosphate pesticides and chemical nerve agents. Due to a reported possible twofold increased risk of ALS in Gulf War veterans and the associations of PON1 polymorphisms with the neurologic symptom complex of the Gulf War syndrome, the authors investigated the association between sporadic ALS (SALS) and PON gene cluster variants in a large North American Caucasian family-based and case-control cohort (N = 1,891). METHODS: Clinically definite and probable ALS was diagnosed according to the revised El Escorial criteria, exclusion of family history of ALS, and SOD1 mutation analysis. Single nucleotide polymorphism (SNP) genotyping was done using TaqMan assays on ABI7900HT. Data were analyzed using SPSS, Haploview, FBAT, and THESIAS. RESULTS: A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. The SNPs rs10487132 and rs11981433 were in strong LD and associated with SALS in the trio (parents-affected child triad) model. The association of rs10487132 was replicated in 450 nuclear pedigrees comprising trios and discordant sibpairs. No association was found in case-control models, and their haplostructure was different from that of the trios with overall reduced LD. Resequencing identified an intronic variant (rs17876088) that differentiated between detrimental and protective SALS haplotypes. CONCLUSION: This study demonstrates evidence of significant association of variants in the Paraoxonase gene cluster with sporadic ALS and is compatible with the hypothesis that environmental toxicity in a susceptible host may precipitate ALS.

    PMID: 16822964 [PubMed - as supplied by publisher]
     
    For more information on this topic go to:  http://www.law.Cornell.edu/uscode/17/107.html

    Parental occupational exposure and the risk of acute lymphoblastic leukemia in offspring in Israel.  (PDF)

    Journal of Occupational and Environmental Medicine, 2006 Feb;48(2):165-74.


    Abadi-Korek I, Stark B, Zaizov R, Shaham J.

    National Institute of Occupational & Environmental Health, Shneider Children's Medical Center of Israel, Petach-Tikva, Israel.

    OBJECTIVE: Parental employment in occupations that have potential exposures to organic solvents or pesticides could be associated with the risk of childhood acute lymphoblastic leukemia (ALL) in their offspring. METHODS: We explored this hypothesis by studying the association with respect to exposure time windows. Our case-control study included 224 children, 112 diagnosed with ALL and 112 matched controls. RESULTS: A significantly higher odds ratio (OR) was found between childhood ALL and reported parental occupational exposures. Analysis of exposures of both parents by exposure time windows revealed significant OR during the preconception and postnatal periods separately. CONCLUSIONS: The results provide support to the association between parental occupational exposures and ALL in their children. These results should be interpreted cautiously because of the small numbers, biases characterizing case-control studies, and the use of hospital-based controls.

    *        Parental exposure to pesticides had a higher risk of developing acute lymphoblastic leukemia (OR- 2.35, 95% CI: 1.10, 5.0)

    *        There was small sample size for pesticides, 45 cases and 14 controls and the authors recommend a larger study.

    Household exposure to pesticides and risk of childhood acute leukaemia (PDF)

    Occupational and Environmental Study, 2006 Feb;63(2):131-4.

    Menegaux F, Baruchel A, Bertrand Y, Lescoeur B, Leverger G, Nelken B, Sommelet D, Hemon D, Clavel J.

    INSERM, U170, IFR69, Villejuif, France. menegaux@vjf.inserm.fr

    OBJECTIVES: To investigate the relation between childhood acute leukaemia and household exposure to pesticides. METHODS: The study included 280 incident cases of acute leukaemia and 288 controls frequency matched on gender, age, hospital, and ethnic origin. The data were obtained from standardised face to face interviews of the mothers with detailed questions on parental occupational history, home and garden insecticide use, and insecticidal treatment of pediculosis. Odds ratios were estimated using unconditional regression models including the stratification variables parental socioeconomic status and housing characteristics. RESULTS: Acute leukaemia was observed to be significantly associated with maternal home insecticide use during pregnancy (OR = 1.8, 95% CI 1.2 to 2.8) and during childhood (OR = 1.7, 95% CI 1.1 to 2.4), with garden insecticide use (OR = 2.4, 95% CI 1.3 to 4.3), and fungicide use (OR = 2.5, 95% CI 1.0 to 6.2) during childhood. Insecticidal shampoo treatment of pediculosis was also associated with childhood acute leukaemia (OR = 1.9, 95% CI 1.2 to 3.3). CONCLUSION: The results reported herein support the hypothesis that various types of insecticide exposure may be a risk factor for childhood acute leukaemia. The observed association with insecticidal shampoo treatment of pediculosis, which has never been investigated before, requires further study.

     

    *        The study aim to investigate an association between pesticide use and childhood leukemia by type of pesticide used (Home Insecticide, Garden Pesticide (insecticide, herbicide, and fungicide) and time of exposure (Pesticide Use During Pregnancy and Pesticide Use During Childhood). 

    *        In the Home Insecticide Use group, there was significant associations amongst those who "Ever" used During Pregnancy, OR = 1.8, 95% CI: 1.2, 2.8, and for those who use During Childhood, OR=1.7, 95% CI: 1.1-2.4.

    *        In the overall Garden Pesticide Use group, there were significant associations for those who  "Ever" used During Childhood, OR = 1.7, 95% CI: 1.1, 2.7.  When the Garden Pesticide Use was subdivided into Insecticide, Herbicide and Fungicide, significant associations were found with Insecticide, OR= 2.4, 95% CI: 1.3, 4.3, and Fungicide, OR= 2.5, 95% CI: 1.0, 6.2).

    *        There were no significant associations found between Leukemia and Garden Pesticide Use During Pregnancy but the number of cases and controls in that group were small.

    *        Significant associations were also found between childhood leukemia and the use of Insecticidal Shampoo to treat Pediculosis, OR=1.9, 95% CI: 1.1, 3.2. When the insecticidal shampoo was subdivided into pyrethroid based, organochlorine based and organophosphorous based, there were significant associations with pyrethroid based, OR=2.0, 95% CI: 1.1, 3.4, but insignificant associations for the other two (again the number of cases and controls were too small).

    Adipose Tissue Concentrations of Persistent Organic Pollutants and the Risk of Prostate Cancer.

    Journal of Occupational & Environmental Medicine. 48(7):700-707, July 2006. Hardell, Lennart MD, PhD; Andersson, Swen-Olof MD, PhD; Carlberg, Michael MSc; Bohr, Louise MD; van Bavel, Bert PhD; Lindstrom, Gunilla PhD; Bjornfoth, Helen MSc; Ginman, Claes MD

    Abstract:

    Objective: We sought to study the concentrations of certain persistent organic pollutants with endocrine-disrupting properties in cases with prostate cancer and controls with benign prostate hyperplasia.

    Methods: Adipose tissue was obtained from 58 cases and 20 controls.

    Results: The median concentration among controls was used as cut-off in the statistical analysis. In the total material, a greater-than median concentration of PCB congener 153 yielded an odds ratio (OR) of 3.15 and 95% confidence interval (CI) of 1.04-9.54 and one chlordane type, trans-chlordane, yielded OR 3.49 (95% CI = 1.08- 11.2). In the group of case subjects with PSA levels greater than the median level of 16.5 ng/mL, PCB 153 was OR 30.3 (95% CI = 3.24-284), hexachlorobenzene OR = 9.84 (95% CI = 1.99-48.5), trans-chlordane OR = 11.0 (95% CI = 1.87-64.9), and the chlordane-type MC6 OR = 7.58 (95% CI = 1.65-34.9). The grouping of PCBs according to structural and biological activity was found to produce significantly increased risks for enzyme and phenobarbital-inducing PCBs and lower chlorinated PCBs in the case group with PSA levels greater than 16.5 ng/mL.

    Conclusions: These chemicals might be of etiologic significance but need to be further investigated. The biological relevance of the arbitrary cut-off point of PSA is unclear.

    (C)2006The American College of Occupational and Environmental Medicine

    Research Finds Exposure To Low Levels Of Pesticides Increases Risk Of Cancer

    (Beyond Pesticides, March 20, 2006)New research at the University of Liverpool suggests that environmental contaminants, such as pesticides, are more influential in causing cancer than previously thought. Previous studies in cancer causation have often concluded that exposure to carcinogenic or endocrine-disrupting chemicals, for example, organochlorines (OC) - found in pesticides and plastics - occurs at concentrations that are too low to be considered a major factor in cancerous disease. Now new research at the University of Liverpool, published in the Journal of Nutritional and Environmental Medicine, has found that exposure even to small amounts of these chemicals may result in an increased risk of developing cancer - particularly for infants and young adults.

    The research consists of systematic reviewing of recent studies and literature concerning the environment and cancer, and is supported by the Cancer Prevention and Education Society. Professor Vyvyan Howard and John Newby, from the University's Department of Human Anatomy and Cell Biology, also found that genetic variations, which can predispose some people to cancer, may interact with environmental contaminants and produce an enhanced effect.

    Professor Howard said: "Organochlorines are persistent organic pollutants (POPs), which disperse over long distances and bioaccumulate in the food chain. For humans the main source of OC exposure is from diet, primarily through meat and dairy products. Children are exposed to dioxin, a by-product of OCs, through food; dioxin and other POPs can also cross the placenta and endanger babies in the womb. Breastfed infants can be exposed to OCs with endocrine disrupting properties that have accumulated in breast milk. Our research looks at involuntary exposure to these chemicals in the air, food and water.

    "Environmental contaminants - in particular synthetic pesticides and organochlorines with hormone-disrupting properties - could be a major factor in causing hormone-dependent malignancies such as breast, testicular and prostate cancers. Preventative measures for these types of cancer have focused on educating the public about the danger of tobacco smoke, improving diet and promoting physical activity. We should now, however, be focusing on trying to reduce exposure to problematic chemicals."

    The research team has also looked at anecdotal evidence, from practicing physicians in pre-industrial societies, which suggests that cancerous disease was rare amongst particular communities, such as the Canadian Inuits and Brazilian Indians. This suggests that cancer is a disease of industrialisation.

    Professor Howard added: "The World Health Organisation estimates that between one and five percent of malignant disease in developed countries is attributed to environmental factors; but our research suggests this figure may have been underestimated."

    Jamie Page, Chairman of Cancer Prevention and Education said: "This research is very important and suggests that there are links between chemicals and cancer. It is our opinion that if progress is to be made in the fight against cancer, far more attention and effort must be made to reduce human exposure to harmful chemicals."

    Professor Howard's finding will be published in the Taylor & Francis Journal of Nutritional and Environmental Medicine.

    Pesticide Exposure and Stunting as Independent Predictors of Neurobehavioral Deficits in Ecuadorian School Children

    Philippe Grandjean, MD, DMSca,b, Raul Harari, MDc, Dana B. Barr, PhDd and Frodi Debes, PsyDa

    PEDIATRICS Vol. 117 No. 3 March 2006, pp. e546-e556 (doi:10.1542/peds.2005-1781)

    a Institute of Public Health, University of Southern Denmark, Odense, Denmark

    b Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts

    c Corporación para el Desarrollo de la Producción y el Medio Ambiente Laboral, Quito, Ecuador

    d National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia

    ABSTRACT

    OBJECTIVES. To examine possible effects on blood pressure, neurological function, and neurobehavioral tests in school-aged children with and without prenatal pesticide exposure in an area where stunting is common.

    METHODS. In a community of Northern Ecuador with intensive floriculture and a high female employment rate, we invited 79 children attending the 2 lowest grades of a public school for clinical examinations. In addition to a thorough physical examination, we administered simple reaction time, Santa Ana dexterity test, Stanford-Binet copying, and Wechsler Intelligence Scale for Children-Revised Digit Spans forward. Maternal interview included detailed assessment of occupational history to determine pesticide exposure during pregnancy. Recent and current pesticide exposure was assessed by erythrocyte acetylcholine esterase activity and urinary excretion of organophosphate metabolites.

    RESULTS. All eligible children participated in the study, but 7 children were excluded from data analysis due to other disease or age >9 years. A total of 31 of the remaining 72 children were classified as stunted based on their height for age. Maternal occupational history revealed that 37 children had been exposed to pesticides during development. After confounder adjustment, prenatal pesticide exposure was associated with a higher systolic blood pressure than in the controls. On neurological examination, 14 exposed children and 9 controls showed ≥1 abnormalities. Of 5 neurobehavioral tests, the Stanford-Binet copying test showed a lower drawing score for copying designs in exposed children than in controls. Stunting was associated with a lower score on this test only, and both risk factors remained statistically significant in a multiple regression analysis with adjustment for demographic and social confounders. Increased excretion of dimethyl and diethyl metabolites of organophosphates was associated with increased reaction time and no other outcomes.

    CONCLUSION. Prenatal pesticide exposure may cause lasting neurotoxic damage and add to the adverse effects of malnutrition in developing countries. The effects differ from those due to acute pesticide exposure.

    Environmental Health Perspectives Volume 114, Number 2, February 2006 Review

    Pesticides and Parkinson's Disease--Is There a Link?

    Terry P. Brown,1 Paul C. Rumsby,2 Alexander C. Capleton,1 Lesley Rushton,1 and Leonard S. Levy1 1Medical Research Council Institute for Environment and Health,University of Leicester, Leicester, United Kingdom; 2National Centre for Environmental Toxicology, WRc-NSF Ltd., Medmenham, Marlow, United Kingdom

    Abstract Parkinson's disease (PD) is an idiopathic disease of the nervous system characterized by progressive tremor, bradykinesia, rigidity, and postural instability. It has been postulated that exogenous toxicants, including pesticides, might be involved in the etiology of PD. In this article we present a comprehensive review of the published epidemiologic and toxicologic literature and critically evaluate whether a relationship exists between pesticide exposure and PD. From the epidemiologic literature, there does appear to be a relatively consistent relationship between pesticide exposure and PD. This relationship appears strongest for exposure to herbicides and insecticides, and after long durations of exposure. Toxicologic data suggest that paraquat and rotenone may have neurotoxic actions that potentially play a role in the development of PD, with limited data for other pesticides. However, both the epidemiology and toxicology studies were limited by methodologic weaknesses. Particular issues of current and future interest include multiple exposures (both pesticides and other exogenous toxicants), developmental exposures, and gene-environment interactions. At present, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists but is insufficient for concluding that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined pesticide and other exogenous toxicant exposure. Key words: epidemiology, literature review, Parkinson's disease, pesticides, toxicology. Environ Health Perspect 114:156-164 (2006). doi:10.1289/ehp.8095 available via http://dx.doi.org/ [Online 7 September 2005]
    Overall Conclusions

    The epidemiologic studies suggest a relatively consistent association between exposure to pesticides and an increased risk of developing Parkinson's Disease (PD), despite differences in study design, case ascertainment and definition, control selection, and pesticide exposure assessment. Particular classes of pesticides found to be associated with PD include herbicides, particularly paraquat, and insecticides; evidence from case reports and case-control studies for an association with exposure to fungicides alone is equivocal. Duration of exposure has also been found to be a risk factor, with those exposed to pesticides for > 10 or 20 years being associated with an increased risk of developing PD. However, in addition to pesticides, several other risk factors are associated with an increased risk of developing PD, including rural living, well-water consumption, and farming. We found no studies that have been able to determine whether these risk factors are independent risk factors or correlated with pesticide exposure.
    The toxicologic evidence suggests that, with certain routes of administration, rotenone and paraquat may have neurotoxic actions that could potentially play a role in the development of PD. These include effects on dopaminergic systems in the SN, and -synuclein aggregation. There is also some evidence that the mechanisms of neurotoxicity associated with exposure to pyrethroids are those that would be suggestive of a role in the development of PD and that dithiocarbamates may interact with other xenobiotic agents to increase neurotoxicity. Studies on various other pesticides suggest that, while theyhave neurotoxic actions, they do not act on systems in the brain of relevance to PD. However, many of these studies reviewed were designed to elicit acute toxicity in order to study the mechanisms of action. We identified no study that administered pesticides at levels comparable with those encountered by pesticides users, nor were the routes of administration those that would be experienced by pesticide users (i.e., oral, inhalation, or dermal). As a result, it is difficult to interpret the relevance of such studies to humans, although the difficulty in modeling a disease such as PD is acknowledged. Of potential toxicologic importance are the few studies that reported dopaminergic neurotoxicity after combined low-level exposure to multiple environmental neurotoxicants, including paraquat and maneb, the combined effects of pesticides and metals on -synuclein, and rotenone and lipopolysaccharide (which may be present due to inflammation or infection). For example, although PD is a disease of aging, the studies of Thiruchelvam et al. (2003) on the developmental exposure to maneb and paraquat indicate that early exposure may lead to PD-like toxic effects upon adult rechallenge. Such studies suggest that exposure to multiple low-level environmental neurotoxicants, perhaps at an early age, may be an etiologic factor in the development of PD.

    Recent toxicologic studies have suggested that multiple genetic and environmental factors could be involved in the etiology of PD. Studies with transgenic mice suggest that the genetic background and expression of the -synuclein gene may have a role to play in neurodegeneration of the SN (Thiruchelvam et al. 2004) and may also lead to increased vulnerability to the neurotoxic effects of the pesticides maneb and paraquat. There is evidence that developmental exposure to pesticides may have an increased neurodegenerative effect as well as making the SN more susceptible to subsequent adult exposure to pesticides, and that combined exposure to pesticides such as maneb and paraquat has a greater neurotoxic effect than either pesticide alone (Cory-Slechta et al. 2005). Other recent studies also suggest some interaction between the neurodegenerative effects of pesticides and inflammatory proteins produced by microglia in the SN (Gao et al. 2003, Liu and Hong 2003).These genetic and environmental factors could be considered in future epidemiologic studies of this multifactorial disease.

    Most of the epidemiologic studies that we reviewed used a case-control design with relatively small numbers of cases. Pesticide exposure history was, by necessity, collected retrospectively, generally using questionnaires. Information and recall bias are inherent limitations of this type of design. The exposure assessments were also limited in their collection of information on the types of pesticides, specific chemicals, and levels of exposure experienced. Of all the studies we reviewed, the two most reliable were large case-control studies that attempted to investigate exposure to different groups of pesticides (Semchuk et al. 1992; Seidler et al. 1996).

    Despite these considerations, it seems unlikely that the relatively consistent association between PD and reported exposure to pesticides observed in the epidemiology studies could be explained wholly by a combination of chance, bias and confounding, and selective reporting. The toxicologic literature indicates several areas that would benefit from further research, including the effect of exposure at different ages, early exposure and developmental changes, the role of inflammatory disease, and the potential for gene-environment interactions. Epidemiologic studies of an appropriate design and size, that collect detailed information on exposure to specific pesticides and other chemicals, including early life exposures, would be required to investigate these issues. Studies to date have not had sufficient power to disentangle the relative importance of intercorrelated risk factors and to evaluate each risk with any confidence. We are aware of several ongoing studies that are addressing some of these areas of concern.
    In conclusion, the weight of evidence is sufficient to conclude that a generic association between pesticide exposure and PD exists, but it is not sufficient to conclude that this is a causal relationship or that such a relationship exists for any particular pesticide compound or combined exposure to pesticides and other exogenous toxicants. In addition, the multifactorial etiology of PD hampers unequivocally establishing the role of any individual contributory causal factor.
    http://ehp.niehs.nih.gov/members/2005/8095/8095.html
    ------------------------------------------------------------------------
    Address correspondence to A.C. Capleton, MRC Institute for Environment and Health, University of Leicester, 94 Regent Rd., Leicester, LE1 7DD, UK. Telephone: 44-0-116-223-1606. Fax: 44-0-116-223-1601. E-mail: acc8@leicester.ac.uk
    Supplementary Material is available online at http://ehp.niehs.nih.gov/docs/2005/8095/supplemental.pdf

    Environ Health Perspect. 2006;114(1):10-17. ©2006 National
    Institute of Environmental Health Sciences
    Posted 01/26/2006

    A Case for Revisiting the Safety of Pesticides: A Closer Look at Neurodevelopment

    Theo Colborn1,2

    1University of Florida, Gainesville, Florida, USA; 2TEDX (The Endocrine Disruption Exchange) Inc., Paonia, Colorado, USA

    Abstract

    The quality and quantity of the data about the risk posed to humans by individual pesticides vary considerably. Unlike obvious birth defects, most developmental effects cannot be seen at birth or even later in life. Instead, brain and nervous system disturbances are expressed in terms of how an individual behaves and functions, which can vary considerably from birth through adulthood. In this article I challenge the protective value of current pesticide risk assessment strategies in light of the vast numbers of pesticides on the market and the vast number of possible target tissues and end points that often differ depending upon timing of exposure. Using the insecticide chlorpyrifos as a model, I reinforce the need for a new approach to determine the safety of all pesticide classes. Because of the uncertainty that will continue to exist about the safety of pesticides, it is apparent that a new regulatory approach to protect human health is needed. Key words: adverse effects, behavior, chlorpyrifos, fetal development, human function, neurodevelopment, pesticides, toxicity. Environ Health Perspect 114:10-17 (2006). doi:10.1289/ehp.7940 available via http://dx.doi.org/ [Online 7 September 2005]

    Introduction

    The U.S. Environmental Protection Agency's (EPA) Office of Pesticide Programs (OPP) estimated that 891 pesticide active ingredients were registered in 1997 (Aspelin and Grube 1999) and that 888 million pounds of pesticide active ingredients were used in the United States in 2001 (Kiely et al. 2004). Few of these chemicals are applied alone but rather are applied in formulations using different combinations of several pesticide active ingredients (MeisterPRO 2004).It is not uncommon for many classes of pesticides, such as insecticides, herbicides, and fungicides, to be used on the same crop (National Agricultural Statistics Service 2005). In the case of insecticides, an adjuvant is often added to the formulations to enhance the intensity of the lethal effect. In the case of herbicides, due to the increasing incidence of plant tolerance to a specific pesticide, some formulations now have as many as three active ingredients (MeisterPRO 2004). Each active ingredient has a specific mode of action for controlling a pest, and each active ingredient has its own possible side effects on the wildlife and humans exposed to it. It is impossible to determine the cumulative risk posed to wildlife and humans as the result of releasing vast amounts of pesticide mixtures into the environment.

    The quality and quantity of the data about the risk posed to humans by individual pesticides vary considerably. In some instances there are numerous studies about the health effects of a particular pesticide in humans and laboratory animals, and for others there are very few. In general, the longer the active ingredient has been on the market, the greater the number of citations in the peer-reviewed literature. Data are sparse when linking pesticides with neurodevelopmental effects other than for the insecticides chlorpyrifos (CPF), parathion, and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT).

    Unlike obvious structural defects, most neurodevelopmental effects cannot be seen at birth or even later in life. Instead, adverse effects on the nervous system are expressed in terms of how an individual behaves or functions. Behavior and function vary considerably from birth through adulthood. Functional deficits are not "on" and "off" conditions but instead range from inconsequential through very mild to very severe to totally debilitating. Consequently, it is difficult to quantify neurodevelopmental impairment. Some of the end points used in the laboratory to detect functional impairment of the brain and nervous system are measured at the gene, cell, biochemical, and/or physiologic levels and often require high-tech instrumentation to quantify. At the human level, a battery of tests is continuing to evolve to measure with increasing sensitivity psychomotor, psychologic, clinical, and psychiatric symptoms to better quantify functional impairment.

    In this article I have two principal purposes in discussingthe inherent risks of using pesticides, the limitations of testing techniques, and the intrinsic incompleteness of all scientific evidence: a) to encourage the use of the open literature about the neurodevelopmental effects of all classes of pesticides when setting the criteria for determining their safety and b) to encourage a more rigorous regulatory approach to protect human and environmental health in the absence of complete scientific certainty. I begin by presenting unequivocal evidence of pesticide exposure to numerous classes of pesticides during development. This is followed by a section on human epidemiology where only weak data are available linking neurodevelopmental impairment with pesticides. Next, I present a case study of how CPF cryptically interferes with brain development one stage after another. This is followed with selected laboratory studies demonstrating that other insecticides as well as other pesticide classes target prenatal brain development similar to CPF and share similar and sometimes diverse impacts on the construction and function of the brain. As the data reveal, not only insecticides but other classes of pesticides, such as herbicides and fungicides, can also interfere with neurodevelopment. In the "Discussion" I challenge the protective value of current pesticide risk assessment strategies in light of the vast numbers of pesticide products on the market with untold numbers of targets and mechanisms of action that can cause neurodevelopmental damage.

    Evidence of Exposure to Pesticides

    Improvements in analytical laboratory equipment and testing procedures have made it easier to detect pesticides and their metabolites at very low concentrations in almost all human tissue. From routinely detecting parts per million (milligrams per kilogram) and more recently to as low as parts per trillion (picograms per kilogram), some laboratories are now able to measure concentrations down to parts per quintillion (femtograms per kilogram). The development of noninvasive sampling methods, such as testing for pesticides and their metabolites in urine, has made it possible to monitor pesticide exposure in infants and children. It is fairly safe to say that every child conceived today in the Northern hemisphere is exposed to pesticides from conception throughout gestation and lactation regardless of where it is born. The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was found in approximately 50% of semen samples provided by 97 Ontario, Canada, farmers (Arbuckle et al. 1999). The herbicides atrazine, metolachlor, alachlor, and 2,4-D and the insecticides diazinon and the CPF analyte 3,5,6-trichloro-2-pyridinol (TCP) were found in semen of men in central Missouri and in urban Minneapolis, Minnesota (Swan et al. 2003); the insecticides chlordane, dichlorodiphenyldichloroethylene (DDE), heptachlor epoxide, and hexachlorobenzene (HCB) were found in ovarian follicular fluid from women undergoing in vitro fertilization in Halifax, Hamilton, and Vancouver, Canada (Jarrell et al. 1993); hexachlorocyclohexane and p,p´-DDE were found in amniotic fluid of women undergoing routine amniocentesis in Los Angeles, California (Foster et al. 2000); and nonpersistent pesticides were found in the amniotic fluid of women referred for amniocentesis in the agricultural San Joaquin Valley, California (Bradman et al. 2003). Pesticides were also found in maternal blood, placental, and umbilical cord blood from women experiencing normal births and stillbirths in India (Saxena et al. 1983), from urban and rural mothers during Caesarian section in the Atoya River basin, Nicaragua (Dorea et al. 2001), and from mothers delivering normal and subnormal weight babies (Siddiqui et al. 2003). In addition, pesticides were found in the breast milk of mothers who delivered by Caesarian section in Nicaragua (Dorea et al. 2001), native Alaskan mothers living an indigenous lifestyle (Simonetti et al. 2001), and women living in southwest Greece (Schinas et al. 2000). A median of 8.26 µg/mL CPF (range, 0.40-458.04 µg/mL) was discovered in the meconium of newborns in Manila, Philippines (Ostrea et al. 2002). Six organophosphate (OP) pesticide metabolites were found in the meconium of 20 newbornsin New York City (Whyatt and Barr 2001). The babies' first bowel movements held concentrations 10-100 times higher than their cord blood. One metabolite, diethylthiophosphate, was found in all 20 samples; another, diethylphosphate, was found in 19 of 20 samples. Both are metabolites of diazinon, CPF, and several other OP insecticides.

    An eastern Washington State research team surveyed OP metabolites in the urine of 210 farmworkers and their children and in dust from their homes and vehicles (Coronado et al. 2004). They segregated farm chores into several classes: harvesting and picking, thinning, loading, transplanting, and pruning. Azinphos-methyl, an OP, was more often found in dust in thinners' homes (92.1% vs. 72.7%) and vehicles (92.6% vs. 76.5%) than in those of workers who did no thinning. Thinners' children had higher concentrations of OP metabolites in their urine, and the metabolites were found more frequently in the children (91.9% detectable in urine), compared to the adults (81.3% detectable; p = 0.002).

    In Seattle, Washington, investigators measured five OP metabolites in 24-hr urine samples of preschool children (2-5 years of age) who were raised on either a predominantly organic (n = 18) or predominantly conventional diet (n = 21) (Curl et al. 2003). Pesticide use was also recorded for each home. Median total dimethylphosphate metabolites (0.06 µmol/L) were significantly higher than median total diethyl alkylphosphates (0.02 µmol/L; p = 0.0001) in the urine. Those children on a conventional diet had levels of dimethylphosphate metabolites six times higher than those of children on an organic diet (medians = 0.17 and 0.03 µmol/L, respectively; p = 0.0003). Median concentrations of both metabolites were almost an order of magnitude higher in the conventionally fed children (0.34 µmol/L vs. 0.04 µmol/L). There were no age differences in the children in the two groups. Home use of pesticides varied, with seven conventional-diet families using OPs versus three organic-diet families using OPs. Although the study group was small and there were difficulties collecting urine samples, this research provides the first empirical data comparing urinary levels of pesticides in youngsters consuming predominantly organic versus conventional diets.

    Human Epidemiology

    Determining a link between fetal exposure to a specific chemical and long-term expression of a change in health poses a monumental challenge when designing epidemiologic studies. For example, one human epidemiologic study uncovered weak but statistically significant associations between neurodevelopmental impairment as a result of exposure to two pesticides during gestation. In a large study of live births (n = 1,532), including 536 children fathered by pesticide applicators, Garry et al. (2002) discovered that "adverse neurologic and neurobehavioral developmental effects clustered among the children born to applicators of the fumigant phosphine [odds ratio (OR) = 2.48; 95% confidence interval (CI), 1.2-5.1]." They also discovered an OR for the herbicide glyphosate (Roundup) of 3.6 (95% CI, 1.3-9.6). Among the children in the phosphine group (n = 290), two were diagnosed with autism, which is high compared with the prevalence nationwide, and five were diagnosed with attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD). It took years of close interaction with the families in this study to be able to track their pesticide exposure without having to resort to recall and to follow the children's functional development (Garry VF, personal communication). The investigators were cautious about their findings and asked for confirmation.

    Another study suggests that CPF might have an effect on head circumference related to the activity of paraoxonase (PON1), an enzyme that can detoxify CPF before it can inhibit acetylcholinesterase (Berkowitz et al. 2004). Babies with a small reduction in head circumference were from mothers whose TCP concentrations were above the detection limit, and their PON1 activity was in the lowest tertile (p = 0.014). Mothers and their infants (n = 404) were recruited from East Harlem and other sections of New York City.

    In a more recent study, Young et al. (2005) looked at the relationship between maternal OP urine metabolites and infant neurodevelopment. They employed a battery of tests using the Brazelton Neonatal Behavioral Assessment Scale for habituation, orientation, motor performance, range of state, regulation of state, autonomic stability, and reflex in 381 infants younger than 62 days of age. Young et al. (2005) found a significant association between increasing total concentrations of maternal urine OP metabolites representing "approximately 80% of OPs used in the Salinas Valley" and increasing numbers of abnormal reflexes in the infants from days 3 to 62. The median age for testing the infants was day 3. Mothers' urine was tested at 14 and 26 weeks during gestation and at day 7 postpartum. The median urine levels of dialkyl phosphate (DAP), dimethyl phosphate, and diethyl phosphate, respectively, were 132, 97, and 21 mol/L during gestation and 222, 160, and 27 nmol/L after delivery. DAP represents the total of diethyl and dimethyl phosphate metabolites. The dimethyl metabolites could reflect exposure to malathion, oxydemeton-methyl, dimethoate, naled, and methidathion, and the diethyl metabolites could reflect exposure to diazinon, CPF, and disulfoton used in the Salinas Valley. It is important to keep in mind that the OPs are readily metabolized, and exposure can vary considerably and most often is transient and unpredictable. The authors noted that there were large within-person variations in urine levels in this study.

    A Case Study: The Cryptic Neurodevelopmental Effects of CPF

    The insecticide CPF is an OP pesticide that has been on the market since 1965 to control insects in agriculture, gardens, building construction, and households. In 2002 the use of CPF was restricted to only agricultural applications, and all domestic use was to be completely phased out by 1 January 2005. The metabolites of CPF have been widely reported in human tissue. In a study based on data from the Centers for Disease Control and Prevention's (CDC 2001) first National Report on Human Exposure to Environmental Chemicals, Hill et al. (1995) found the CPF analyte TCP in 82% of urine samples (n = 1,000) from a broad sample of the U.S. population between the ages of 20 and 59 years from all regions of the country. The CDC's Second National Report on Human Exposureto Environmental Chemicals (CDC 2003) states that the levels of TCP were similar to levels presented in the first National Report on Human Exposure to Environmental Chemicals (CDC 2001) but gave no statistics concerning the extent of exposure across the population. Like the other OP insecticides, CPF inhibits the enzyme acetylcholinesterase, which destroys acetylcholine, the neurotransmitter that activates cholinergic neurons. These are an important group of nerve cells that control signals in the peripheral nervous system and in the brain and spinal cord. If acetylcholine is not inactivated immediately by the activity of acetylcholinesterase, it overstimulates the neurons, and tremors, convulsions and death can follow.

    As scientists probed deeper into the activity of CPF, a wealth of information surfaced from laboratory studies about its effects on the development and function of the brain and nervous system in embryos, fetuses, and young animals. Although many of the studies were performed on rats and there are differences in the ontogeny of specific parts of the brain between rats and humans, the development of the rat brain through postnatal day (PND) 21 provides a model for the development of the human brain through to birth.

    A series of reports starting in 1991 confirmed that CPF is a cholinesterase inhibitor and that neonatal rats were more sensitive than adults when exposed to a single maximum tolerated dose (Pope and Chakraborti 1992; Pope et al. 1991, 1992). These studies also confirmed that the fetus recovers quicker than the adult from cholinesterase inhibition, suggesting that the fetus would be protected from CPF if all the adverse effects were due to cholinesterase inhibition alone. Lassiter et al. (1998), however, wrote that although the fetus could recover faster between repeated doses of CPF, this was only an "illusion that the fetal compartment is less affected than the maternal compartment." Realizing that something other than cholinesterase inhibition was affecting the fetus, a team from Duke University led by Theodore Slotkin gradually began to demonstrate that other mechanisms of action of CPF alter prenatal development of the brain and behavior and that the embryo and fetus are sensitive to cholinesterase inhibition at doses that would not be toxic to an adult (Qiao et al. 2003; Slotkin 2004). These studies provided information about how the brain develops and functions and also provided a chronology of how CPF interferes at successional stages of brain development (Qiao et al. 2002). This team also demonstrated that CPF-oxon, the active metabolite of CPF, is the compound that causes cholinesterase inhibition and that the actual neuroteratogen is CPF (see Slotkin 2004 for a step-by-step description of how their CPF research progressed).

    Slotkin and colleagues demonstrated that as the brain and nervous system are constructed and programmed, there are numerous points in time and at sites where CPF could interfere. CPF attacks the neurons that appear in the earliest stage of brain and central nervous system (CNS) development (Qiao et al. 2004). Neurons process information and are the signaling or transmitting elements in the nervous system. Damage to neurons at this early stage may not be expressed until years later. For example, a brief subtoxic dose of CPF [1 or 5 mg/kg body weight (bw)/day] during neurulation can cause behavioral alterations during adolescence and adulthood (Icenogle et al. 2004). And, although some early symptoms of CPF exposure disappear during certain stages of development, different neurologic symptoms can appear later in life (Qiao et al. 2002, 2003, 2004).

    Glial cells that appear later than neurons during early development were shown to be more vulnerable than neurons to CPF (Qiao et al. 2002; Roy et al. 2004). There are more than twice as many glial cells (> 200 billion) in the body than neurons. Glial cells come in many varieties; they are supportive cells critical for normal development and function and serve as a "scaffold" for migration of cells during tissue construction [see Barone et al. (2000) on brain development]. Glial cells also provide nutrition to the neurons and provide a link with the immune system, responding to damage by acting as scavengers of pathogens and neuronal debris. CPF preferentially targets the glial cells among the cells it attacks (Garcia et al. 2002).

    Slotkin and colleagues repeatedly demonstrated that CPF toxicity is not limited to cholinesterase inhibition alone but can act by other mechanisms. For example, in vitro and in vivo studies at three levels of development from DNA to the cell and the whole animal revealed that CPF is far more toxic than previously thought because of this wider range of activity (Crumpton et al. 2000). CPF impairs the binding to DNA of nuclear transcription factors (AP-1 and Sp1) that modulate cell replication and differentiation. When undifferentiated and differentiated neurons were exposed to CPF, the response of some transcription factors varied. Although the activity of one set of cells might not be affected, the activity of another set of cells might be significantly reduced. An independent study at Johns Hopkins University (Schuh et al. 2002) confirmed the ability of CPF to alter the activity of another nuclear transcription factor in cortical neurons, the Ca2+/cAMP response element binding protein (CREB), which is critical for cell survival and differentiation during development and is critical for memory. CPF increased the activated level of CREB at 0.01 nM, well below the level at which cholinesterase inhibition is expressed and below the typical level of human exposure. Schuh et al. (2002) also demonstrated that CPF-oxon did not cause the alteration, supporting the conclusion of Crumpton et al. (2000) that CPF is more than a cholinesterase inhibitor. Crumpton et al. (2000) also demonstrated that the CPF effects on the development of the forebrain in the rat, which reaches its peak stage of development during gestation, were not as severe as the effects on the cerebellum, which reaches its peak 2 weeks after birth. The cerebellar changes in the later stages of development, however, could not have been the result of cholinesterase inhibition because the cerebellum is not innervated with cholinergic receptors like the forebrain is (Crumpton et al. 2000).

    Much of the research undertaken by Slotkin and colleagues demonstrated that models of adult toxicity do not extrapolate to fetuses and would not predict the vulnerability of the embryo to TCP and CPF (Aldridge et al. 2004, 2005a). The ever-changing state of the embryo makes it a more sensitive model for toxicity and a better predictor of long-term, delayed effects. Slotkin and colleagues have demonstrated that the embryo and fetus reveal innumerable mechanisms of action of toxicity that could not be detected in an adult animal. For example, in a series of in vitro studies, a 25% increase in reactive oxygen species (ROS) was found 10 min after undifferentiated glial C6 cells were exposed to CPF (Garcia SJ et al. 2001). During some stages of development, selected regions of the brain are vulnerable to CPF by interference with the G-protein in the adenylyl cyclase (AC) cascade by disrupting nuclear transcription DNA binding (Meyer et al. 2003; Slotkin 1999). CPF caused abnormal tissue/cell development in cultured rat embryos through vacuolation of the cytoplasm (Roy et al. 1998). CPF, CPF-oxon, and TCP inhibit DNA synthesis in PC12 cells (typical neuronal cells) and C6 cells (typical glial cells), having a greater effect on the glial cells, with the exception of the TCP (Qiao et al. 2001). Qiao et al. (2001) also showed that CPF is a stronger DNA synthesis inhibitor than CPF-oxon, although it is a weaker cholinesterase inhibitor. Confirming again that certain regions of the developing brain were more susceptible than others, Qiao et al. (2001) found that CPF and TCP suppress DNA synthesis in the epithelium of the forebrain and inhibit neural cell replication. These studies also revealed that serum binding proteins can be protective of DNA antimitotic activity, but because fetuses and newborns have lower concentrations of serum proteins than adults, they could be more vulnerable.

    In a series of whole-animal studies looking at damage in rats from the embryo to the adult, Slotkin and colleagues demonstrated again that assays using adult animals cannot predict the long-term delayed effects in the offspring. For example, within hours after 9.5-day-old embryos were exposed to CPF, they showed clear signs of damage that was restricted to the primordial brain (Roy et al. 1998). Upon histologic examination, Roy et al. (1998) found apoptosis and altered mitotic figures, along with gross disruption of the architecture of the developing brain, all in the absence of any gross morphologic defects in the other parts of the embryo. As these animals matured, CPF damage was demonstrable in a wide variety of brain regions. The most vulnerable target was the hippocampus, with the damage expressed both as deficits in nerve activity and as corresponding behavioral abnormalities (Icenogle et al. 2004). Dosing an adult animal similarly would not have provoked these effects of fetal origin.

    The complexity of the toxicity of CPF became more apparent as sex-related differences began to appear in in vivo assays. The sex-related changes occur when CPF exposure takes place during gestation days (GD) 17-20 (late gestation) and PND1-4 and again at PND11-14. The timing of this exposure in the rat is comparable to human brain development during the perinatal and neonatal period (Aldridge et al. 2004; Meyer et al. 2004a; Slotkin et al. 2001). Late prenatal exposure to CPF has also been shown to cause long-term sex-specific changes in cognitive performance (Levin et al. 2002). Adolescent and adult females were more vulnerable to CPF, based on their number of errors during working- and reference-memory tasks. Levin et al. (2002) also found profound differences between animals exposed to 1 mg/kg and 5 mg/kg CPF, reflecting a U-shaped dose curve. The lowest dose was the most potent in this case, although the highest dose caused the most inhibition of fetal brain cholinesterase. The non-monotonic dose-response curve discovered in the assay, combined with the fact that the results were not dependent on cholinesterase inhibition, raises questions about indirect effects of CPF and its metabolites on the endocrine system via the brain. However, as Slotkin (personal communication) pointed out, hormesis cannot be ruled out until further research proves otherwise. In light of their findings, Levin et al. (2002) noted the need for childhood and adolescent maturation studies and for the development of more sex-selected end points.

    At a concentration somewhat higher than human exposure, 50 µg/mL CPF in vitro induces the release of norepinephrine from rat brain synaptosomes (Dam et al. 1999). Studies using whole animals confirmed that the release of norepinephrine inhibits synaptogenesis, a condition that persists to adulthood and is sex specific, long after exposure ceases and cholinesterase activity is restored (Levin et al. 2002). Aldridge et al. (2004) showed that CPF administered during GD9-12 up-regulated serotonin (5-hydroxytryptamine; 5-HT) receptors (5-HT-1 and 5-HT-2) and interfered with the 5-HT protein transporter from the neural tube stage through to adulthood. But during GD17-20, CPF initiated larger effects in regions with greater numbers of 5-HT nerve terminals, which were found more in males. This response continued through PND1-4. In contrast, the 5-HT protein transporter was downregulated in females (Aldridge et al. 2004). Aldridge et al. (2005a,b) performed studies demonstrating abnormalities of 5-HT-related behaviors in developing rats exposed to CPF. The research that preceded this report mapped out the ontogeny of serotonin receptors in the brainstem and forebrain (Aldridge et al. 2003). The authors pointed out that serotonin disruption has been linked to appetitive and affective disorders, and the biologic significance of these findings needs to be clarified. These disorders have been the focus of increasing research attention in recent years as the result of the increasing use of prescription and and illicit mind-altering drugs.

    Other Pesticide Products That Interfere with Neurodevelopment

    There are numerous opportunities during gestation where insecticides and products from several other chemical classes can alter the purpose of a cell, tissue, organ, or system function in the brain or CNS, much like the discoveries presented for CPF.

    Herbicides. Over the past 15 years, an Argentinian research team has produced a series of reports on 2,4-D that is comparable to the research on CPF. This team discovered that exposure during lactation to the herbicide 2,4-DBE (the butyl ester of 2,4-D) can alter brain production of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in adulthood (Bortolozzi et al. 2001; Evangelista de Duffard et al. 1990; Garcia G et al. 2001). Concentrations of both dopamine and serotonin changed transiently if the animals were exposed only through birth (69 mg/kg bw/day from GD6 to birth; 15 days) and permanently if delivered to the offspring through breastfeeding as well from GD6 to weaning (30 days). Duffard et al. (1996) and Rosso et al. (2000) found that 2,4-D interfered with myelination in the brain as the result of lactational exposure. This caused changes in behavior patterns that included apathy, reduced social interaction, repetitive movements, tremors, and immobility in pups exposed to 2,4-D (Bortolozzi et al. 1999; Evangelista de Duffard et al. 1995). They also discovered that the serotoninergic and dopaminergic effects occurred during postnatal brain development, similar to the effects of CPF. Bortolozzi et al. (1999) and Evangelista de Duffard et al. (1995) also found 2,4-D in breast milk of 2,4-D-fed mothers and in the stomach content, brain, and kidney of 4-day-old pups (Sturtz et al. 2000).

    Insecticides. Cassidy et al. (1994) reported that the lowest dose of chlordane used in their studies (100, 500, 5,000 ng/g/day both prenatally and postnatally) caused a dose-

    dependent reduction in testosterone levels in females in adulthood. The lowest dose they used was 10 times lower than the U.S. EPA's lowest observed adverse effect level (LOAEL) for neurologic effects (1,000 ng/g) and 50 times lower than the U.S. EPA's LOAEL for developmental effects (5,000 ng/g) of chlordane (Cassidy et al. 1994). Females exhibited improved spatial abilities and auditory startle-evoked responses more similar to male responses, and slight increases in body weight. Changes in male mating behavior included shortening of latency to intromission and increased intromissions. The authors speculated that pesticides structurally similar to chlordane cause masculinization of function and behavior in both sexes because the pesticides mimic the sex steroids or change their plasma levels through other enzyme systems. The two lower doses in this study prompted greater change than the highest dose for auditory startle response, mating behavior, and body weight.

    Methoxychlor (MXC), an insecticide whose toxicity depends on its conversion to several metabolites, was considered to be an estrogen for many years and only recently was discovered to have antiestrogenic and androgenic properties as well. To measure neurodevelopmental impacts, Palanza et al. (2002) fed pregnant CD-1 mice environmentally relevant doses of MXC (0.02, 0.2, and 2.0 µg/g mother bw/day) from GD11 to GD17 and examined them on postpartum days 2-15. Mothers fed the lowest dose spent less time nursing than the controls, possibly reflecting the inverted U-shaped dose-response curve expressed by endocrine disruptors. At late adolescence the pups exhibited a reduction in novelty seeking (both the environment and objects), with a difference between males and females (Palanza et al. 1999). Male sexual aggression was reduced at puberty but returned to normal in adulthood. The reduction in aggressive behavior in the periadolescent male CD-1 mouse as a result of MXC exposure (20 µg/kg/day) occurred at a dose 100 times lower than the dose at which the Agency for Toxic Substances and Disease Registry (ATSDR 2002) deemed would cause no harm to humans in 1994. The ATSDR recently withdrew this minimum risk level in light of new evidence on MXC.

    Dopaminergic neurons in the substantia nigra project to and release dopamine to the corpus striatum of the brain. This section of the brain integrates neuromuscular and behavioral information and is involved in the control of locomotor activity, exploration, and novelty-induced behavior. It also influences social-sexual interactions such as aggression and maternal behavior. The loss of dopamine function in the neurons connecting the corpus striatum with the midbrain of humans is the cause of Parkinson disease. Male offspring of mice exposed to 20 µg/kg/day MXC had fewer dopaminelike receptors in their corpus striatum and were less active than control females (vom Saal et al. 2003). Females exposed to the same concentrations showed a malelike profile in reactivity to novelty. Similar changes in males and females were seen in mice exposed to o,p´-DDT in the same study. In an unrelated study, Lamberson et al. (2001) discovered increased locomotor behavior in offspring of Sprague-Dawley rats administered 0.5 mg/kg/day MXC throughout gestation.

    Prenatal exposure to aldrin also causes delayed neurologic impairment that extends through to adulthood. Castro et al. (1992) administered 1 mg/kg aldrin subcutaneously to female rats daily from conception to birth and tested their pups on PND1-2 and again on PND90. On PND90, the animals showed loss of locomotor control and behavioral change(s). Aldrin was not measurable in the animals at the time they were tested.

    Paraoxon is the oxidized metabolite of parathion and a potent OP cholinesterase inhibitor. Chronic paraoxon exposure (0.1, 0.15, or 0.2 mg/kg subcutaneously) during a stage of rapid cholinergic brain development from PND8 to PND20 in male Wistar rats led to reduced dendritic spine density in the hippocampus without obvious toxic cholinergic signs in any of the animals (Santos et al. 2004). Some animals in the two highest dose groups died in the early days of the study. All doses caused retarded perinatal growth, and brain cholinesterase activity was reduced 60% by PND21.

    Johansson et al. (1995) showed that a single exposure to a pesticide before or shortly after birth can sensitize the offspring to low doses of other pesticides later in life, even though there are no immediate changes in the structure and function of the nervous system at the time of exposure. Only as the exposed individual matures do irreversible alterations in structure and function become evident. The researchers exposed mice to one dose of DDT (0.5 mg/kg bw orally) on PND10 and then at 5 months of age exposed them to bioallethrin (0.7 mg/kg bw) (Johansson et al. 1995) or paraoxon (0.7 or 1.4 mg/kg bw) for 7 days (Johansson et al. 1996). When tested 2 months later, at 7 months of age, the offspring exhibited changes in spontaneous behavior and cholinergic muscarinic receptor density in the cerebral cortex, which led to impairment in learning and memory (Eriksson and Talts 2000). Again, the neurodevelopmental damage was not seen immediately, but instead took 2 months to be expressed. PND10 in the mouse is equivalent to the end of the second trimester in the human. It is during this stage, from the third trimester of pregnancy through 2 years of age in humans, when the neurotransmitter system in the CNS goes through a growth spurt (Eriksson 1997). Throughout these studies the animals showed no clinical signs of toxic symptoms, and the doses used for adult treatment in these studies had no immediate effect on the adult. The dose of DDT used in this studyis in the range that human infants might be exposed to during lactation today (Smith 1999). Even though the functional and structural outcomes in the above studies are similar, it should be remembered that they were caused by different mechanisms. For example, bioallethrin causes harm by prolonging sodium channel openings, whereas paraoxon inhibits acetylcholinesterase activity; but they both caused similar neuronal changes, which raises questions about the combined effects of pesticide mixtures on development. These studies support the premise that the differences in susceptibility of adults to pesticides may not be genetic, but rather that susceptibility to pesticides can be acquired by low-dose pesticide exposure earlier in life.

    Insecticide and acaricide. Rat pups displayed deficits in learning and retention of memory after exposure to the organochlorine insecticide and acaricide endosulfan (6 mg/kg bw) on PND2-25 (Lakshmana and Raju 1994). The concentrations of the neurotransmitters, noradrenalin, dopamine, and serotonin in the olfactory bulb, hippocampus, visual cortex, brainstem, and cerebellum either increased or decreased depending on the days of examination, PND10 and PND25.The authors ruled out acetylcholinesterase inhibition as the cause of the alterations in the production of the neurotransmitters because they found no differences in acetylcholine activity in any of the regions of the brain used in the study. They suggested that endosulfan directly led to a "re-altering" of the construction of those parts of the brain. By PND25, as the differentiation and organization of the observed tissues proceeded in the presence of endosulfan, the rats' performance became significantly compromised.

    Fungicides. Gray and Ostby (1998) provided an excellent overview of how prenatal exposure to a fungicide can alter sexual behavior and function in adulthood, even though growth and viability are not compromised. The neurobehavioral alterations quantified in the studies they reviewed include activity level, aggression, mounting frequency, and completed intromissions. In a study using the fungicide vinclozolin, Gray et al. (1994) reported that 100% of the exposed males failed to attain intromission, although there was no reduction in mounting behavior. In subsequent studies, newborn male and female rats were injected on PND2 and PND3 with 200 mg/kg vinclozolin and observed for social behavior on PND36 and PND37 (Hotchkiss et al. 2002). Both males and females exhibited changes in play behavior. Females became involved in increased rough-and-tumble play, a behavior imprinted by male hormones in the brain during early development. Conversely, the males' rough-and-tumble play was reduced, and they behaved more like unexposed females. Because only one dose was used, this study does not indicate the lowest dose needed to initiate these changes. More recently, on PND34 Colbert et al. (2005) found significantly increased nape contact, pounce, pin, and wrestle play behavior in male offspring of females exposed to 6 and 12 mg/kg bw/day vinclozolin from GD14 to PND3. At a maternal dose of 1.5 mg/kg bw/day vinclozolin, there was a significant increase in penile dysfunction in adulthood. Future studies should include more than one dose, preferably over several orders of magnitude, to take into account the susceptibility and sensitivity of the developing animal.

    Discussion

    There is a great deal of uncertainty about the neurodevelopmental effects of pesticides among the human studies presented here. Exposure has become too complex because of the hundreds of pesticide active ingredients on the market, confounded by background exposure to industrial chemicals that share similar effects. In addition, functional changes are expressed over a continuum, making it difficult to document the damage which often is expressed as more than one lesion and at different intervals or stages of development. The pesticides discussed here, with the exception of DDT, are still widely used in the United States despite these data. Although this information is available, the U.S. EPA has rarely used the open literature in its risk assessments, generally using only data submitted by manufacturers. Industry continues to use traditional toxicologic protocols that test for cancer, reproductive outcome, mutations, and neurotoxicity, all crude end points in light of what is known today about functional end points. In using manufacturer data, the U.S. EPA misses almost all delayed developmental, morphologic, and functional damage of fetal origin and, in the case of CPF and all OPs, continues to rely primarily on blood cholinesterase inhibition data in risk assessments (Zheng et al. 2000). The U.S. EPA should accept nonguideline, open literature to determine the toxicity of a chemical. For example, Brucker-Davis (1998) published a comprehensive review of the open literature in which she found 63 pesticides that interfere with the thyroid system--a system known for more than a century to control brain development, intelligence, and behavior. Yet, to date, the U.S. EPA has never taken action on a pesticide because of its interference with the thyroid system.

    It would be difficult to find another pesticide in use today that has been as systematically studied as CPF. The amazing litany of diverse mechanisms discovered in the series of CPF studies raises serious questions about the safety of not only CPF and the other OPs but all pesticides in use today. Most astounding is the fact that a large part of CPF's toxicity is not the result of cholinesterase inhibition, but of other newly discovered mechanisms that alter the development and function of a number of regions of the brain and CNS. These findings send a warning that even though an OP pesticide like CPF may have a very high EC50 (concentration that produces 50% of the maximum possible effective response)for acute toxicity as a result of cholinesterase inhibition, it may have other toxic strategies that are far more egregious than cholinesterase inhibition. This raises a question about the value of using EC50 values if they do not represent the most sensitive end point. Qiao et al. (2003) warn that "developmental neurotoxicity consequent to fetal or childhood CPF exposure may occur in settings in which immediate symptoms of intoxification are absent." They also point out that in the case of CPF, damage is not always global (referring to the entire brain) but may only interfere in specific regions of the brain during development, which could increase the difficulty of detecting the damage. S.J. Garcia et al. (2001) state that "measurement just of cholinesterase activity is a questionable approach in assigning an appropriate index of safety."

    The knowledge gained from a decade of the CPF/brain studies by Slotkin and colleagues and the 2,4-D/brain studies by Evangelista de Duffard and co-workersnot only demonstrates the insidious nature of CPF and 2,4-D exposure, but it also demonstrates the weaknesses in current standard practices for determining the safety of a pesticide or any other synthetic chemical. These discoveries demonstrate that a much larger battery of tests must be used when determining the safety of commercial pesticides. Even a U.S. EPA analysis of developmental neurotoxicity studies stated that the U.S. EPA's current developmental neurotoxicologic testing protocol is "not a sensitive indicator of toxicity to the offspring" and urged the U.S. EPA "to further consider if it will use literature data" (Makris et al. 1998). In this case, "literature data" refers to all of the peer-reviewed reports concerning the pesticide impacts on neurodevelopment that heretofore have not been used for risk assessment by the agency. In the case of CPF and 2,4-D, it appears that those who reviewed the data failed to understand its significance or had other reasons to ignore it. The U.S. EPA needs to convene a panel of independent experts to review these studies for applicability to determine if and how they can be used for registration.

    Laboratory studies have clearly revealed neurologic damage after exposure to specific pesticides and in some studies at concentrations equivalent to ambient exposure. Even so, the animal testing for regulatory purposes that takes place today does not attempt to detect adverse health effects at the concentrations at which humans are exposed. Instead, the highest concentrations of chemicals tested are those that can be used without killing the animals or reducing the test mother's weight and her reproductive ability.In most animal studies the pesticides are administered at high oral or subcutaneous doses orally, not reflecting that, for most humans and wildlife, exposure could in many instances be dermal or via inhalation and, in many cases, over a long period of time at low doses. The U.S. EPA currently requires chronic toxicity studies, but it is locked into using high doses to elicit effects and has not overcome the difficulty of detecting effects from chronic or ambient exposure or low doses. In addition, the human pharmacokinetics of pesticide exposure can either enhance or reduce the health impacts depending on individual variations. In some cases the major or minor metabolites are more toxic than the parent compound, which is listed as the active ingredient.

    In a recent study, Bowers et al. (2004) found a different profile of developmental neurotoxicity between polychlorinated biphenyls (PCBs; such as Aroclor 1254) alone and with a mixture of organochlorine pesticides. Very low doses of the chemicals together delayed ear opening, affected geotaxis, and reduced grip strength. Ultimately, mortality, growth, thyroid function, and neurobehavioral development were affected. It is safe to say that there are very few people in the developed world today who are not carrying PCBs in their bodies. If animal testing continues to be used for determining the safety of pesticides, at least one group of the test animals should be exposed to PCBs before testing the pesticides for their ability to cause unpredictable interactive effects such as those described above.

    It should be pointed out that the same signaling systems (AC cAMP) involved in the sex-selective changes in brain development have also been shown to alter heart and liver function in adulthood (Meyer et al. 2004a, 2004b). The AC system is ubiquitous throughout the body. In the future, the most efficient, comprehensive assays will take advantage of the fact that most chemicals have more than one effect in one system. Cross-disciplinary teams will be required to design these assays so that every organ system is carefully screened for damage. And most important, this will reduce by thousands the numbers of animals needed for testing. However, improved neurodevelopmental tests with laboratory animals will not fulfill their greatest potential if they are not backed up by better batteries of tests to detect functional disabilities in children. Such new, sophisticated quantitative tests are now available and are being updated regularly. These tests go beyond diagnostic testing to "performance evaluation" and are designed to detect the subtle effects of chronic, low-dose exposure (Davidson et al. 2000).

    In conclusion, an entirely new approach to determine the safety of pesticides is needed. It is evident that contemporary acute and chronic toxicity studies are not protective of future generations. The range of doses used in future studies must be more realistic, based on levels found in the environment and human tissue. In this new approach, functional neurologic and behavioral end points should have high priority, as well as the results published in the open literature. In every instance, the impacts of transgenerational exposure on all organ systems must be meticulously inventoried through two generations on all contemporary-use pesticides and new pesticide coming on the market. To protect human health, however, a new regulatory approach is also needed that takes into consideration this vast new knowledge about the neurodevelopmental effects of pesticides, not allowing the uncertainty that accompanies scientific research to serve as an impediment to protective actions.

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    Pesticide mixtures, Endocrine disruption, and amphibian declines: Are we underestimating the impact?

    Abstract

    Amphibian populations are declining globally at an alarming rate. Pesticides are among a number of proposed causes for these declines. Though a sizable data-base examining effects of pesticides on amphibians exists, the vast majority of these studies focus on toxicological effects (lethality, external malformations, etc.) at relatively high doses (ppm). Very few studies focus on effects such as endocrine disruption at low concentrations. Further, the majority of studies examine exposures to single chemicals only. The current study examined nine pesticides (four herbicides, two fungicides, and three insecticides) used on cornfields in the mid-western US. Effects of each pesticide alone (0.1 ppb) or in combination were examined. In addition, we examined atrazine and S-metolachlor (0.1 or 10 ppb each) or the commercial formulation, Bicep II Magnum, which contains both of these herbicides. These two pesticides were examined in combination because they are persistent throughout the year in the wild. We examined larval growth and development, sex differentiation, and immune function in leopard frogs (Rana pipiens). In a follow-up study, we also examined the effects of the nine-compound mixture on plasma corticosterone levels in male African clawed frogs (Xenopus laevis).

    Though some of the pesticides inhibited larval growth and development, the pesticide mixtures had much greater effects. Larval growth and development were retarded, but most significantly, pesticide mixtures negated or reversed the typically positive correlation between time to metamorphosis and size at metamorphosis observed in controls: Exposed larvae that took longer to metamorphose were smaller than their counterparts that metamorphosed earlier. The nine-pesticide mixture also induced damage to the thymus, resulting in immunosuppression and contraction of flavo-bacterial meningitis. The study in X. laevis revealed that these adverse effects may be due to an increase in plasma levels of the stress hormone, corticosterone. Though it cannot be determined whether all of the pesticides in the mixture contribute to these adverse effects or whether some pesticides are "effectors", some are "enhancers", and some are "neutral", the current study revealed that estimating ecological risk and the impact of pesticides on amphibians using studies that examine single pesticides at high concentrations, only, may lead to gross underestimations of the role of pesticides in amphibian declines.

    Household exposure to pesticides and risk of childhood acute leukaemia

    F Menegaux1, A Baruchel2, Y Bertrand3, B Lescoeur4, G Leverger5, B Nelken6, D Sommelet7, D Hémon1 and J Clavel1

    1 INSERM, U170, IFR69, Villejuif, France
    2 Department of Pediatric Hematology, Saint-Louis Hospital, Paris, France
    3 Department of Pediatric Hematology, Debrousse Hospital, Lyon, France
    4 Department of Pediatric Hematology-Immunology, Robert Debré Hospital, Paris, France
    5 Department of Pediatric Hematology, Armand Trousseau Hospital, Paris, France
    6 Department of Pediatric Hematology-Oncology, Jeanne de Flandre Hospital, Lille, France
    7 Department of Pediatric Hematology, Brabois Hospital, Nancy, France

    Correspondence to:
    Dr F Menegaux
    INSERM U170, 16, av. Paul Vaillant-Couturier, F-94807 Villejuif Cedex; menegaux@vjf.inserm.fr

    Accepted 6 October 2005

    ABSTRACT

    Objectives: To investigate the relation between childhood acute leukaemia and household exposure to pesticides.

    Methods: The study included 280 incident cases of acute leukaemia and 288 controls frequency matched on gender, age, hospital, and ethnic origin. The data were obtained from standardised face to face interviews of the mothers with detailed questions on parental occupational history, home and garden insecticide use, and insecticidal treatment of pediculosis. Odds ratios were estimated using unconditional regression models including the stratification variables parental socioeconomic status and housing characteristics.

    Results: Acute leukaemia was observed to be significantly associated with maternal home insecticide use during pregnancy (OR = 1.8, 95% CI 1.2 to 2.8) and during childhood (OR = 1.7, 95% CI 1.1 to 2.4), with garden insecticide use (OR = 2.4, 95% CI 1.3 to 4.3), and fungicide use (OR = 2.5, 95% CI 1.0 to 6.2) during childhood. Insecticidal shampoo treatment of pediculosis was also associated with childhood acute leukaemia (OR = 1.9, 95% CI 1.2 to 3.3).

    Conclusion: The results reported herein support the hypothesis that various types of insecticide exposure may be a risk factor for childhood acute leukaemia. The observed association with insecticidal shampoo treatment of pediculosis, which has never been investigated before, requires further study.

    Abbreviations: ALL, acute lymphoblastic leukaemia; ANLL, acute non-lymphoblastic leukaemia; IARC, International Agency for Research on Cancer

    Keywords: epidemiology; case control study; childhood leukaemia; pesticide exposure

    Leukaemia is the most common cancer in childhood with an incidence rate of 43.1 per 1 000 000 per year in France1 and, with the exception of ionising radiation and certain rare genetic syndromes, its aetiology remains largely unknown. Several studies2–8 and two reviews of epidemiological studies9,10 have suggested that household pesticide exposure may be associated with childhood leukaemia. The studies considered different definitions of exposure (home or garden pesticide use, pesticides overall, insecticides), different periods of exposure (pregnancy, childhood, or both), different subtypes of the cases included (acute lymphoblastic leukaemia: ALL or acute non-lyphoblastic leukaemia: ANLL) and different age groups (<9 years, <10 years, <15 years, <18 years). Residential pesticide exposure has also been associated with other childhood cancers (lymphoma, brain tumour, neuroblastoma, Wilm's tumour, and Ewing's sarcoma). Moreover, the International Agency for Research on Cancer (IARC) considers the "spraying and application of non-arsenical insecticides entailing exposures" to be, as a whole, probably carcinogenic to humans.11

    The present study was designed to assess the role of environmental and genetic factors in the aetiology of childhood acute leukaemia. This paper analyses the relation between pesticide exposure and childhood acute leukaemia.

    METHODS

    Cases and controls
    The detailed study design has been reported elsewhere.12 Briefly, the cases were children under the age of 15 years hospitalised following recent diagnosis (<2 months) of primary leukaemia between 1995 and 1999 in the hospitals of Lille, Lyon, Nancy, and Paris (France). Special care was paid to selecting an appropriate hospitalised control group. The hospital based design of the study was chosen because case and control blood samples were required. Controls were children hospitalised in the same hospital as cases, mainly in orthopaedic and emergency departments, and mainly residing in the same area as cases (that is, the catchment area of the hospital). Many different diagnostic categories were included in order to avoid selection biases in the event that a particular disease was related to the exposures of interest. However, children hospitalised for cancer or a major congenital malformation were not eligible for the study, because those diseases may share risk factors with leukaemia.

    Recruitment was frequency matched by age, gender, hospital, and ethnic origin (white, North African, other). Two case and two control mothers refused to participate. The physicians requested that the interviewers refrain from contacting the mothers of 13 cases (nine ALL and four ANLL) whose condition was critical. All the control mothers were contacted. One control child who had been adopted was excluded. Thus, a total of 280 incident cases of acute leukaemia confirmed by cytology and 288 controls were included in the study.

    Data collection
    The mothers of the cases and controls were interviewed face to face by specifically trained medical doctors using a standard questionnaire. The questions addressed the parents' sociodemographic characteristics, the child's pre- and post-natal characteristics and medical history, the familial history of cancer and autoimmune diseases, and the parents' occupations and habits.

    The questions relating to pesticide exposure covered pregnancy and the period from birth to diagnosis, and included home insecticide and garden pesticide (insecticides, herbicides, and fungicides) use by the mother. The questions on pesticide use at home and in the garden were closed questions: "Did you regularly use insecticides at home?", "Did you use, yourself, gardening chemicals: fertilizer, herbicides, insecticides, fungicides, others?". The questionnaire also addressed the parents' occupations during pregnancy and during childhood of study subjects.

    The index child's direct pesticide exposure to pediculosis treatments during childhood was also determined through an open question on the types of treatment received.

    Statistical analysis
    All the analyses were performed using the SAS software packages (version 9.1, Cary, NC, USA). Odds ratios (OR) were estimated using unconditional logistic regression models including the stratification variables: gender, age, hospital, and ethnic origin. Potential confounding by sociodemographic characteristics (maternal educational level and parental socioprofessional category), place of residence (rural: <=5000 inhabitants and urban: >5000 inhabitants), and type of housing (apartment or house) was considered in the various analyses. Adjustments were also performed on other variables previously identified as related to acute leukaemia in this study (familial history of cancer or autoimmune disease, early common infections, daycare attendance, prolonged breast feeding, and residence in the vicinity of a gas station or garage).12–16

    Only seven cases and four controls came from outside the catchment area of the hospital (3% v 1%, p = 0.37). When we restricted the analyses to cases and controls residing inside the catchment area of the hospital, the results were unchanged. Thus, we decided to present results on the entire study population.

    RESULTS

    Study population
    Out of the 280 cases included in the study, acute lymphoblastic leukaemia (ALL) was diagnosed in 240 and acute non-lymphoblastic leukaemia (ANLL) in 40 cases.

    Most of the controls (89%) were recruited in an orthopaedic or emergency department (table 1Go). Sixty per cent of the cases were 2–6 years old, versus 55% of the controls. Good case control comparability of maternal and paternal schooling was obtained after adjustment for stratification variables (table 1Go). The case and control groups contained the same proportion of working mothers and had similar socioprofessional category distributions.

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    Table 1 Sample description for the cases and controls

    Parental occupational exposure to pesticides
    Five cases and three controls had a parent (mother or father) who was occupationally exposed to pesticide during the childhood of the index child. Only two cases and one control had a mother who was occupationally exposed to pesticide during the pregnancy of the index child.

    Home insecticide use
    We observed a significant association between childhood acute leukaemia and home insecticide use (OR = 1.8, 95% CI 1.2 to 2.8) during pregnancy and OR = 1.7 (95% CI 1.1 to 2.4) during childhood) (table 2Go). When the exposure periods were considered individually, home insecticide use was only significantly associated with childhood acute leukaemia when exposure occurred during both pregnancy and childhood (OR = 1.6 (95% CI 0.8 to 3.3) during pregnancy only, OR = 1.4 (95% CI 0.8 to 2.3)) during childhood only, and OR = 2.0 (95% CI 1.2 to 3.1) during pregnancy and childhood).

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    Table 2 Home and garden pesticide use and childhood acute leukaemia by period of exposure

    Garden pesticide use
    Overall, pesticide use for gardening during childhood (OR = 1.7, 95% 1.1 to 2.7) was associated with acute leukaemia. Garden insecticide use during childhood and garden fungicide use during childhood were associated with childhood acute leukaemia (OR = 2.4 (95% 1.3 to 4.3), OR = 2.5 (1.0 to 6.2), respectively), while garden herbicide use was not (OR = 1.4, 95% CI 0.8 to 2.4). When the periods of exposure were considered individually, garden pesticide use was associated with childhood acute leukaemia when exposure occurred during both pregnancy and childhood (OR = 1.2 (95% CI 0.5 to 3.0) during pregnancy only, OR = 1.5 (95% 0.9 to 2.5) during childhood only, and OR = 5.6 (95% CI 1.6 to 20) during pregnancy and childhood. Garden insecticide use remained associated with acute leukaemia only when the period of exposure was during childhood (OR = 0.6 (95% CI 0.1 to 7.6) during pregnancy only, OR = 1.4 (95% CI 1.3 to 4.7) during childhood only, and OR = 3.4 (95% CI 0.7 to 17) during pregnancy and childhood).

    Insecticide treatments for pediculosis
    Pediculosis during childhood was more frequently reported for cases than for controls with ORs of 1.5 (95% CI 0.9 to 2.5) for one episode and 1.9 (95% CI 1.1 to 3.3) for two or more episodes (table 3Go). Overall, the use of shampoos to treat pediculosis was associated with childhood leukaemia (OR = 1.9, 95% CI 1.1 to 3.2). Various insecticidal shampoos were reported and were pyrethroid based (65 cases and 55 controls, OR = 2.0 (95% CI 1.1 to 3.4)), organochlorine based (six cases and four controls, OR = 2.1 (95% CI 0.5 to 8.7)), and organophosphorus based (five cases and 10 controls, OR = 0.7 (95% CI 0.2 to 2.4)). The estimates were similar for ALL and ANLL.

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    Table 3 Pediculosis during childhood and risk of childhood acute leukaemia

    Adjustments
    The estimates were unchanged when the use of insecticides at home, for gardening, and to treat pediculosis were considered together in the same model. There was no change in the results after adjustment for parental socioprofessional categories, parental educational levels, place of residence (urban or rural), or type of housing (apartment or house). Moreover, adjusting separately or simultaneously for familial history of cancer or autoimmune disease, frequent early common infections, daycare attendance, prolonged breastfeeding, and residence in the vicinity of a gas station or garage—factors which were previously related to childhood acute leukaemia in the present study—did not modify the results.

    The results remained stable over the age groups and were similar for ALL and ANLL.

    Missing values
    The data on the shampoos used to treat pediculosis were missing from about 10% of the questionnaires. A sensitivity analysis was carried out to evaluate the potential impact of those missing data on the estimates. When the missing data were all considered exposures and then all considered non-exposures, the odds ratios remained greater than 1, and were close to significance or significant: OR = 1.5 (95% CI 0.9 to 2.5) and OR = 2.0 (95% CI 1.2 to 3.3), respectively. In the extreme and unlikely scenario that the missing data were non-exposures for cases and exposures for controls, the odds ratio would be 1.2 (95% CI 0.7 to 1.9).

    DISCUSSION

    The present study evidenced associations between childhood acute leukaemia and three sources of exposure to insecticides: home insecticide use, garden insecticide use, and insecticide use for pediculosis. The number of parents who were occupationally exposed to pesticides was too small to allow further analyses.

    The size of the present study enabled detection of minimum odds ratios of 1.6, 1.9, and 2.2 for control exposure prevalences of 20%, 10%, and 5%, respectively. These prevalences are of the same order of magnitude as those for home insecticide use during pregnancy and during childhood (21% and 29%, respectively), garden insecticide use during pregnancy and during childhood (1% and 5%, respectively), and insecticidal pediculosis treatment during childhood (25%).

    The oncology departments recruit patients from more distant places than do control departments, and this could have introduced bias. In order to keep cases and controls comparable in terms of socioeconomic category and rural/urban status, most of the children (all but seven cases and four controls) were living in the same administrative region as the hospital location.

    The case and control mothers were very similar with respect to education, occupation, socioeconomic status, and place of residence. The results were unchanged after additional adjustment for the parents' socioprofessional categories, educational levels, place of residence (urban or rural), or type of housing (apartment or house). The use of standardised questionnaires and similar interviewing conditions for case and control mothers reduced potential differential misclassifications.

    Pesticide exposure is a growing public concern which might induce recall bias. However, our study took place in the period 1995–99 when the subject was far less in the media in France than it is now. Nevertheless, a recall bias cannot strictly be ruled out. The information on shampoos to treat pediculosis may be unreliable, but probably in the same way for the cases and controls.

    A variety of possible confounding factors were incorporated in the model in order to test the consistency of the association between insecticide exposure and acute leukaemia. The factors included variables that had previously been shown to be related to childhood acute leukaemia in the present study. The variables related to home or garden insecticide use and pediculosis treatment were also incorporated simultaneously. Adjusted for separately or taken together, none of those variables had any influence on the results. With respect to shampoos for pediculosis, sensitivity analyses showed that loss of association would only occur for unlikely distributions of missing data and that the OR would still be 1.2 in the extreme scenario, in which all the missing case data consisted of non-exposures and all the missing control data consisted of exposures.

    The shampoos used to treat pediculosis could have contained three types of insecticide, possibly in combination: pyrethroid, organochlorinated (lindane), and organophosphorus (malathion) insecticides. To the authors' knowledge, no previous study has investigated direct childhood pesticide exposure due to insecticidal shampoos. The results reported herein therefore need to be replicated and investigated further.

    The results for residential pesticide exposure are consistent with previously published studies. Home pesticide use during pregnancy or childhood was associated with childhood acute leukaemia in the six studies which investigated that exposure.2–6,8 Leiss and Savitz (1995) reported an association with pesticide strip use during pregnancy and childhood.4 The authors cited dichlorvos, a specific insecticide used in pesticidal strips, which is carcinogenic in animals and classed as possibly carcinogenic for humans by the IARC. In addition, "spraying and application of non-arsenical insecticides entailing exposures" have been classified as probably carcinogenic by the IARC.11

    The association with garden pesticide use is less consistent: two studies found an association between childhood leukaemia and garden pesticide use during pregnancy,3,5 one study found an association with garden pesticide use during childhood,3 and three studies did not find any association irrespective of the period of exposure.4,6,8 The incidence of childhood cancer was not related to local agricultural pesticide use in an ecological study.17 However, the same authors subsequently conducted a case control study and reported associations between childhood leukaemia and local agricultural use of two common types of pesticide, metham sodium (OR = 2.05 (95% CI 1.01 to 4.17)), and difocol (OR = 1.83 (95% CI 1.0 to 3.22)).18

    In conclusion, the findings of the present study reinforce the hypothesis already suggested by the literature that household pesticide exposure may play a role in the aetiology of childhood acute leukaemia. At this stage, no specific product can be singled out and a causal relation remains questionable. However, the consistency of our results and the results from previous studies suggests that it may be opportune to consider preventive action.

    ACKNOWLEDGEMENTS

    This work was supported by grants from INSERM, the French Ministère de l'Environnement, the Association pour la Recherche contre le Cancer, the Fondation de France, the Fondation Jeanne Liot, the Fondation Weisbrem-Berenson, the Ligue Contre le Cancer du Val de Marne, and the Ligue Nationale Contre le Cancer.

    We are grateful to Drs Diane Farkas, Kamila Kebaïli, Anne Lambilliotte, Dominique Steschenko, Martine Zagouri, and Naïma Belkacem, who conducted the interviews, and to Martine Valdes, Isabelle Jaussent, Laurence Mandereau, and Dominique Ridondelli for technical assistance. We also thank the heads of the departments who helped us to include their patients as controls: Professors Bensahel, Bérard, Carlioz, Deberigny, Felipe, Herbault, Lascombes, Pouliquen, and Rigault. We are grateful to Andrew Mullarky for his skilful revision of the manuscript.

    FOOTNOTES

    Competing interests: none.

    Ethics approval: the present study has been approved by the National Commission for Data protection and the Liberties (no 339392) and by the ethic committee (no 94.0356).

    REFERENCES

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    3. Infante-Rivard C, Labuda D, Krajinovic M, et al. Risk of childhood leukaemia associated with exposure to pesticides and with gene polymorphisms. Epidemiology 1999;10:481–7.[CrossRef][Medline]

    4. Leiss JK, Savitz DA. Home pesticide use and childhood cancer: a case-control study. Am J Public Health 1995;85:249–52.[Abstract]

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    8. Meinert R, Schuz J, Kaletsch U, et al. Leukaemia and non-Hodgkin's lymphoma in childhood and exposure to pesticides: results of a register-based case-control study in Germany. Am J Epidemiol 2000;151:639–46 discussion 47–50.[Medline]

    9. Daniels JL, Olshan AF, Savitz DA. Pesticides and childhood cancers. Environ Health Perspect 1997;105:1068–77.[Medline]

    10. Zahm SH, Ward MH. Pesticides and childhood cancer. Environ Health Perspect 1998;106 (Suppl 3) :893–908.[Medline]

    11. IARC. Monographs on the evaluation of carcinogenic risk to humans, vol 53 1991.

    12. Perrillat F, Clavel J, Auclerc MF, et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br J Cancer 2002;86:1064–9.[CrossRef][Medline]

    13. Perillat-Menegaux F, Clavel J, Auclerc MF, et al. Family history of autoimmune thyroid disease and childhood acute leukaemia. Cancer Epidemiol Biomarkers Prev 2003;12:60–3.[Abstract/Free Full Text]

    14. Perrillat F, Clavel J, Jaussent I, et al. Family cancer history and risk of childhood acute leukaemia (France). Cancer Causes Control 2001;12:935–41.[CrossRef][Medline]

    15. Perrillat F, Clavel J, Jaussent I, et al. Breast-feeding, fetal loss and childhood acute leukaemia. Eur J Pediatr 2002;161:235–7.[CrossRef][Medline]

    16. Steffen C, Auclerc MF, Auvrignon A, et al. Acute childhood leukaemia and environmental exposure to potential sources of benzene and other hydrocarbons; a case-control study. Occup Environ Med 2004;61:773–8.[Abstract/Free Full Text]

    17. Reynolds P, Von Behren J, Gunier RB, et al. Childhood cancer and agricultural pesticide use: an ecologic study in California. Environ Health Perspect 2002;110:319–24.[Medline]

    18. Reynolds P, Von Behren J, Gunier RB, et al. Agricultural pesticide use and childhood cancer in California. Epidemiology 2005;16:93–100.[CrossRef][Medline]

    Study Finds Job-Related Exposure to Pesticide (Diazinon) May Increase Cancer Risk

    Date Published: November 30, 2005
    Source: Newsinferno News Staff

    According to a new study by the  Agricultural Health Study , a government funded program established in 1993 to examine the negative effects of pesticides on farming families in Iowa and North Carolina, regular exposure to the pesticide diazinon may cause lung and other types of cancer.

    Diazinon (an organophosphate) is a pesticide that is derived from nerve gases that were introduced during World War II. In 2004 the chemical was removed from use in garden and lawn products because of evidence the substance could cause neurological disorders and other health problems that were not cancerous.

    The findings of the recent study suggest a link between diazinon and lung cancer. Data showed that in 2002, 301 of 4,961 men who were exposed to the chemical in the workplace had developed lung cancer while only 968 of 18,145 of the subjects without daily exposure to the chemical got cancer.

    In the report published in the American Journal of Epidemiology, Dr. Michael C. R. Alavanja from the National Cancer Institute in Rockville, Maryland, and his colleagues stated: "We found evidence of an association of lung cancer and leukemia risk with increasing lifetime exposure days to diazinon."

    The results corroborate a previous report by Agricultural Health Study which covered a less extensive period of time. The findings were also not impacted when cigarette smoking was accounted for, indicating that cigarettes do not explain the increased risk of lung cancer.

    Although in a 1997 review of diazinon, the EPA classified the chemical as "not likely a human carcinogen" based on studies in rodents, the results from Agricultural Health Study confirms other laboratory and epidemiologic data that suggests the pesticide does pose a risk.

    In response the EPA has offered to institute new restrictions on diazinon's use. According to the 2004 data, about 4 million pounds of the chemical was applied agriculturally in America.

    Using Biological Markers in Blood to Assess Exposure to Multiple Environmental Chemicals for Inner-City Children 3 - 6 Years Old

    Ken Sexton1*, John L. Adgate, Ann L. Fredrickson, Andrew D. Ryan, Larry L. Needham, and David L. Ashley, University of Minnesota School of Public Health, MMC 807, Mayo building    420 Delaware Street, S.E.,  Minneapolis, MN 55455-0392

    Abstract

    Concurrent exposure to a mixture of more than 50 environmental chemicals was assessed by measuring the chemicals or their metabolites in blood of 43 ethnically diverse children (3 - 6 years old) from a socioeconomically disadvantaged neighborhood in Minneapolis. Over a two-year period, additional samples were collected every 6 - 12 months from as many children as possible. Blood samples were analyzed for 11 volatile organic compounds (VOCs), 2 heavy metals - lead (Pb) and mercury (Hg), 11 organochlorine (OC) pesticides or related compounds, and 30 polychlorinated biphenyl (PCB) congeners. The evidence suggests that numerous VOCs originated from common sources as did many PCBs. Longitudinal measurements indicate that between-child variance was greater than within-child variance for 2 VOCs (benzene, toluene), for both heavy metals (Pb, Hg), for all detectable OC pesticides, and for 15 of the measured PCB congeners (74, 99, 101, 118, 138-158, 146, 153, 156, 170, 178, 180, 187, 189, 194, 195). Despite the relatively small sample size, highest measured blood levels of 1,4-dichlorobenzene, styrene, m-/p-xylene, lead, mercury, heptachlor epoxide, oxychlordane, p,p'-DDE, trans-nonachlor, and PCBs 74, 99, 105, 118, 138, 146, 153, 156, 170, and 180 were comparable to or higher than 95th percentile measurements of older children and adults from national surveys. Results demonstrate that cumulative exposures to multiple environmental carcinogens and neurotoxins can be comparatively high for children from a poor inner-city neighborhood

    "MXC [methoxychlor]  has an adverse effect on these mice similar to that of DES, a synthetic estrogen…"

    http://www.eurekalert.org/pub_releases/2005-09/yu-cpm091205.php

    Press Release

    September 12, 2005

    Contact: Karen N. Peart
    karen.peart@yale.edu
    203-432-1326
    Yale University

    Common pesticide may reduce fertility in women

    Methoxychlor (MXC), a common insect pesticide used on food crops, may interfere with proper development and function of the reproductive tract, leading to reduced fertility in women, researchers at Yale School of Medicine write in the August issue of Endocrinology.

    The researchers found that MXC, which was manufactured as a safer replacement for the now-banned DDT, alters the estrogen-regulated gene Hoxa10 in the reproductive tract and reduces the ability of the uterus to support embryo implantation. The researchers used mice and then human cell lines to confirm their findings.

    MXC is a man-made pesticide used to kill flies, mosquitoes, cockroaches and other insects, and is applied directly to food crops, livestock, home gardens and pets. It is one of a large number of chemicals that can mimic the action of hormones and in some instances interfere with endocrine function.

    Some of these endocrine disruptors bind estrogen receptors and adversely affect reproductive tract development, which is heavily influenced by estrogen. MXC and other chemicals like DDT have been shown in other studies to induce abnormalities in tissue development and function in the female reproductive tract.

    "MXC has an adverse effect on these mice similar to that of DES, a synthetic estrogen," said senior author Hugh S. Taylor, M.D., associate professor in the Division of Reproductive Endocrinology and Infertility in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine. "Female offspring of women exposed to DES were more likely to have an abnormally shaped cervix, were more prone to cancer of the vagina, miscarriages, early labor and other complications."

    Other authors on the study included Xiaolan Fei and Hajin Chung

    ###

    Citation: Endocrinology, 146: 3445-3451 (August 2005)

    Pyrethroids used indoor-ambient monitoring of pyrethroids following a pest control operation.

    Institute of Hygiene, Heinrich-Heine-University Dusseldorf, Germany. gabriele.leng.gl@bayerindustry.de

    House dust and airborne particles (PM) were sampled before (T1) and 1 day (T2), 4-6 months (T3) as well as 10-12 months (T4) after a pest control operation (PCO). Cyfluthrin was applied in 11, cypermethrin in 1, deltamethrin in three and permethrin in four interiors. The pyrethroid concentrations in house dust and PM were measured by GC/MS with a detection limit for all pyrethroids of 0.5 mg/kg house dust and of 1 ng/m3 PM for deltamethrin and permethrin and 3 ng/m3 PM for cyfluthrin and cypermethrin. A general background concentration of permethrin (95th percentile: 5.9 mg/kg) and cyfluthrin (95th percentile: 34.9 mg/kg) in house dust was found. In general, an appropriately performed PCO lead to an increase of pyrethroids in house dust as well as in PM, in some cases up to 1 year after application. One day after the application the cyfluthrin concentration increased significantly from 0.25 (T1) to 33.8 mg/kg house dust (T2) and up to 4.9 ng/m3 in PM. The permethrin concentration increased significantly from 4.3 to 70 mg/kg in house dust and up to 18.1 ng/m3 in PM, deltamethrin increased to 54.5 mg/kg and 20.8 ng/m3 and cypermethrin to 14 mg/kg and 45.7 ng/m3. Thereafter a continuous decrease could be observed during the time course of 1 year. After 1 year the permethrin concentration in house dust was still 1/5 of the T2 concentration, whereas for cypermethrin and cyfluthrin only 1/14 and 1/23 of the T2 concentration were found. Deltamethrin was not detected at all after T2. Moreover, the data of this study showed significant, positive correlations between pyrethroids in house dust and in airborne particles especially one day after PCO.


    PMID: 15971858 [PubMed - indexed for MEDLINE]   abstract:

    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15971858&query_hl=2

    full text:

    http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B7GVY-4FJV22M-6-B&_cdi=20443&_user=10&_orig=browse&_coverDate=05%2F13%2F2005&_sk=997919996&view=c&wchp=dGLbVlb-zSkWA&md5=1ef0994b6e908d553494682f9ae22e20&ie=/sdarticle.pdf

    Sustained Exposure to the Widely Used Herbicide Atrazine: Altered Function and Loss of Neurons in Brain Monoamine Systems

    Veronica M. Rodriguez, Mona Thiruchelvam, and Deborah A. Cory-Slechta

    Environmental and Occupational Health Sciences Institute, and Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, USA

    Abstract

    The widespread use of atrazine (ATR) and its persistence in the environment have resulted in documented human exposure. Alterations in hypothalamic catecholamines have been suggested as the mechanistic basis of the toxicity of ATR to hormonal systems in females and the reproductive tract in males. Because multiple catecholamine systems are present in the brain, however, ATR could have far broader effects than are currently understood. Catecholaminergic systems such as the two major long-length dopaminergic tracts of the central nervous system play key roles in mediating a wide array of critical behavioral functions. In this study we examined the hypothesis that ATR would adversely affect these brain dopaminergic systems. Male rats chronically exposed to 5 or 10 mg/kg ATR in the diet for 6 months exhibited persistent hyperactivity and altered behavioral responsivity to amphetamine. Moreover, when measured 2 weeks after the end of exposure, the levels of various monoamines and the numbers of tyrosine hydroxylase-positive (TH+) and -negative (TH-) cells measured using unbiased stereology were reduced in both dopaminergic tracts. Acute exposures to 100 or 200 mg/kg ATR given intraperitoneally to evaluate potential mechanisms reduced both basal and potassium-evoked striatal dopamine release. Collectively, these studies demonstrate that ATR can produce neurotoxicity in dopaminergic systems that are critical to the mediation of movement as well as cognition and executive function. Therefore, ATR may be an environmental risk factor contributing to dopaminergic system disorders, underscoring the need for further investigation of its mechanism(s) of action and corresponding assessment of its associated human health risks. Key words: atrazine, dopamine, hypothalamus, locomotor activity, microdialysis, prefrontal cortex, striatum, substantia nigra, unbiased stereology.

    Environ Health Perspect 113:708-715 (2005). doi:10.1289/ehp.7783 available via http://dx.doi.org/ [Online 24 February 2005]

    Science, Vol 308, Issue 5727, 1466-1469 , 3 June 2005 [DOI: 10.1126/science.1108190]

    Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility

    Matthew D. Anway, Andrea S. Cupp,* Mehmet Uzumcu,† Michael K. Skinner‡

    Transgenerational effects of environmental toxins require either a chromosomal or epigenetic alteration in the germ line. Transient exposure of a gestating female rat during the period of gonadal sex determination to the endocrine disruptors vinclozolin (an antiandrogenic compound) or methoxychlor (an estrogenic compound) induced an adult phenotype in the F1 generation of decreased spermatogenic capacity (cell number and viability) and increased incidence of male infertility. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined (that is, F1 to F4). The effects on reproduction correlate with altered DNA methylation patterns in the germ line. The ability of an environmental factor (for example, endocrine disruptor) to reprogram the germ line and to promote a transgenerational disease state has significant implications for evolutionary biology and disease etiology.

    Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, WA 99164–4231, USA.

    * Present address: Department of Animal Science, University of Nebraska, Lincoln, NE 68583–0908, USA.

    †Present address: Department of Animal Science, Rutgers University, 84 Lipman Drive, New Brunswick, NJ 08901–8525, USA.

    ‡To whom correspondence should be addressed. E-mail: skinner@mail.wsu.edu


    Int Immunopharmacol. 2005 Feb;5(2):263-70.

    Influence of pyrethroids and piperonyl butoxide on the Ca(2+)-ATPase activity of rat brain synaptosomes and leukocyte membranes.



    Grosman N, Diel F.

    Department of Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. fing@farmakol.ku.dk

    Pyrethroids are widely used insecticides of low acute toxicity in mammals but the consequences of long-term exposure are of concern. Their insecticidal action is related to neurotoxicity and, in addition, there are indications of mammalian immunotoxicity. In order to clarify structure-activity relationships of the membrane interactions of pyrethroids, the present study compared the influence of selected pyrethroids, i.e. permethrin and the more water soluble esbiol (S-bioallethrin), both type I, and cyfluthrin, type II, on the Ca(2+)-ATPase activity of rat brain synaptosomes and peritoneal leukocyte membranes. The pyrethroids were tested alone as well as mixed with the enhancing substance piperonyl butoxide (PBO) at concentration ratios of 1:5 and 1:10. At the highest concentration tested, permethrin (10 microM) alone inhibited the ATPase activity of leukocyte membranes by 20%, whereas the synaptosomes were affected less. Esbiol and cyfluthrin alone did not affect either membrane preparation significantly, whereas PBO (50 microM) alone caused 10-15% inhibition. Mixtures of either pyrethroid with PBO inhibited the ATPase activity of both types of membranes (up to 40% inhibition) in a synergistic manner, which always tended to be supra-additive. With esbiol a true potentiation took place. The synergistic interaction between pyrethroid and PBO was most apparent with mixtures of a concentration ratio of 1:5. The ATPase activity of leukocyte membranes tended to be more susceptible to inhibition than that of synaptosomes. The results are in accordance with the assumption that the mammalian toxicity of pyrethroids can be ascribed to a general disturbance of cell membrane function in neuronal tissue. The results indicate that it may also be the case in the immune apparatus.

    PMID: 15652757 [PubMed - in process]

    New Pesticide Isomer Study Shows New Breakdown and Toxicity Risks

    The findings of this study were published in a paper titled "Enantioselectivity in Environmental Safety of Current Chiral Insecticides" in last week's online edition of the Proceedings of the National Academy of Sciences.

    (Beyond Pesticides, January 14, 2005) Researchers at the University of California, Riverside have demonstrated that isomers - or the mirror-image structures - of some pesticides, although chemically identical, have very different biological and environmental impacts between the two sides. This may have significant implications for regulation of these pesticides.

    The environmental risks of pesticides have been traditionally evaluated on the basis of their specific chemical structure, according to Jay Gan, a UCR professor of environmental chemistry. He found, however, that this group, known as chiral pesticides, including many widely used organophosphates and synthetic pyrethroids, pose previously uncalculated toxic risks due to the differing biological reactions of the isomers in the environment.

    A characteristic of chiral compounds is that they occur as isomers with two (or more) identical but mirror-image structures that, as Gan's research indicates, while chemically identical, may behave biologically differently. These mirror-image molecules are known as enantiomers. Currently about 25 percent of pesticides fall into this classification and this ratio is expected to increase as new products are being introduced into the market.

     Dr. Gan published the paper in cooperation with a team of UCR colleagues including Daniel Schlenk, professor of aquatic ecotoxicology; Soil Physics Professor, William A. Jury; and visiting professor Weiping Liu.

    Dr. Gan and his colleagues at UC Riverside examined chiral insecticides that are widely used today. They examined five common insecticides, including organophosphates, such as profenofos, and synthetic pyrethroids, such as permethrin. For all these compounds, one of the optical isomers, or enantiomers, was consistently over 10 times more toxic than the other to Ceriodaphia, a small crustacean often used to assess water toxicity.

    The researchers also found that a specific enantiomer lingered longer in the environment than the other enantiomers, making one enantiomer of permethrin almost twice as prevalent in sediment or runoff water. This means that the environmental impact of these pesticides may depend on the behavior of a particular enantiomer instead of the whole compound, the team concluded.

    Dr. Gan also believes that knowing about such selectivity would also be valuable for the chemical industry. For instance, if only one enantiomer is known to contribute to the pest control efficacy, it would be advantageous to manufactured products containing just the active component. The rate of use may be cut in half. "The difference in terms of pesticide regulation and future R&D directions could be pretty drastic for chiral pesticides," said Dr. Gan.

    TAKE ACTION: Let EPA Administrator Michael Leavitt know that you want the Environmental Protection Agency to take this new information regarding pesticide isomers into account and error on the side of caution in regulating pesticides.

    Are household chemicals connected to the rise in asthma?

    23/12/2004

    Frequent use of household cleaning products and other chemicals in the home could be linked to cases of asthma among Britain's children.

    A new study of respiratory health among young children has shown a clear connection between breathing problems and their mothers' use of a range of common products such as bleach, paint stripper and carpet cleaners.

    In the 10 per cent of families who used the chemicals most frequently, the children were twice as likely to suffer wheezing problems as the families where they were used least.

    The exact chemicals involved have not been identified, but the researchers say they have established a clear link between use of chemicals in the home and wheezing in young children - which can go on to develop into asthma

    The findings, published today in the journal Thorax, are based on research involving 7,019 families from the Children of the 90s project at the University of Bristol.

    The report's author Dr Andrea Sherriff says that other studies throughout Europe and the USA have demonstrated an increased risk of asthma in people working as cleaners.

    "While research has concentrated on the working environment, there is virtually no data available on the effect of frequent use of chemical -based products in the home on the respiratory health of young children.

    "It has been put forward that the indoor air environment may play an important role in the increasing asthma problem due to the fact that people, especially mothers with young children, spend so much of day indoors."

    During the study, pregnant women were asked to report how often they used a list of chemical-based products.

    The 11 most common were disinfectant (used by 87.4%), bleach (84.8%), carpet cleaner (35.8%), window cleaner (60.5%), dry cleaning fluid (5.4%), aerosols (71.7%), turpentine/white spirit (22.6%), air fresheners - spray, stick or aerosol (68%), paint stripper (5.5%) , paint or varnish (32.9%) and pesticides/insecticides (21.2%).

    For each family - researchers calculated the total chemical burden according to how frequently they used each product - then they compared it with each mother's report on whether her child had experienced wheezing with whistling on his or her chest

    Upto the age of 3 1/2 years, 71.2% children never wheezed, 19.1% appeared to wheeze as babies but not when they were older, 3.5 per cent developed wheezing problems after the age of 2 1/2 and 6.2 per cent (432 children) had persistent wheeze throughout.

    After taking into account a range of other factors - including whether the parents smoked, damp housing, and family history of asthma - the study found a significant association between the children who suffered persistent wheezing and the mother's use of these chemicals. The more frequently the chemicals were used - the higher the risk that the young child would have persistent wheezing.

    Dr Sherriff said: "These findings suggest that children whose mothers made frequent use of chemical-based domestic products during pregnancy were more likely to wheeze persistently throughout early childhood, independent of many other factors.

    "Further research will identify whether this effect persists into later childhood and will attempt to identify the specific components responsible."




    Sherriff A, Farrow A, Golding J, ALSPAC Study Team, Henderson AJ. Frequent use of chemical household products is associated with persistent wheezing in preschool-age children. Thorax 2005; 60: 45-9.

    NOTES


    For further information contact ALSPAC PR and Communications:
    Nick Kerswell , Sally Watson or Anne Gorringe 0117 33 16731 MOBILE 07967 390808

    See www.alspac.bristol.ac.uk

    http://www.alspac.bris.ac.uk/press/household_chemicals.shtml



    http://news.bbc.co.uk/2/hi/health/4115617.stm

    Early-Life Environmental Risk Factors for Asthma: Findings from the Children's Health Study

    Muhammad Towhid Salam, Yu-Fen Li, Bryan Langholz, and Frank Davis Gilliland
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

    Early-life experiences and environmental exposures have been associated with childhood asthma. To investigate further whether the timing of such experiences and exposures is associated with the occurrence of asthma by 5 years of age, we conducted a prevalence case-control study nested within the Children's Health Study, a population-based study of > 4,000 school-aged children in 12 southern California communities. Cases were defined as physician-diagnosed asthma by age 5, and controls were asthma-free at study entry, frequency-matched on age, sex, and community of residence and countermatched on in utero exposure to maternal smoking. Telephone interviews were conducted with mothers to collect additional exposure and asthma histories. Conditional logistic regression models were fitted to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Asthma diagnosis before 5 years of age was associated with exposures in the first year of life to wood or oil smoke, soot, or exhaust (OR = 1.74; 95% CI, 1.02-2.96), cockroaches (OR = 2.03; 95% CI, 1.03-4.02), herbicides (OR = 4.58; 95% CI, 1.36-15.43), pesticides (OR = 2.39; 95% CI, 1.17-4.89), and farm crops, farm dust, or farm animals (OR = 1.88; 95% CI, 1.07-3.28). The ORs for herbicide, pesticide, farm animal, and crops were largest among children with early-onset persistent asthma. The risk of asthma decreased with an increasing number of siblings (ptrend = 0.01). Day care attendance within the first 4 months of life was positively associated with early-onset transient wheezing (OR = 2.42; 95% CI, 1.28-4.59). In conclusion, environmental exposures during the first year of life are associated with childhood asthma risk. Key words: asthma, breast-feeding, cockroach, day care, farm environment, herbicide, pesticide, sibship size, wood smoke. Environ Health Perspect 112:760-765 (2004). [Online 9 December 2003]

    Glyphosate Biomonitoring for Farmers and Their Families: Results from the Farm Family Exposure Study

    John F. Acquavella,1 Bruce H. Alexander,2 Jack S. Mandel,3 Christophe Gustin,1 Beth Baker,2 Pamela Chapman,4 and Marian Bleeke1
    1Monsanto Company, St. Louis, Missouri, USA; 2School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA; 3Rollins School of Public Health, Emory University, Atlanta, Georgia, USA; 4Exponent Corporation, Menlo Park, California, USA

    Abstract

    Glyphosate is the active ingredient in Roundup agricultural herbicides and other herbicide formulations that are widely used for agricultural, forestry, and residential weed control. As part of the Farm Family Exposure Study, we evaluated urinary glyphosate concentrations for 48 farmers, their spouses, and their 79 children (4-18 years of age). We evaluated 24-hr composite urine samples for each family member the day before, the day of, and for 3 days after a glyphosate application. Sixty percent of farmers had detectable levels of glyphosate in their urine on the day of application. The geometric mean (GM) concentration was 3 ppb, the maximum value was 233 ppb, and the highest estimated systemic dose was 0.004 mg/kg. Farmers who did not use rubber gloves had higher GM urinary concentrations than did other farmers (10 ppb vs. 2.0 ppb). For spouses, 4% had detectable levels in their urine on the day of application. Their maximum value was 3 ppb. For children, 12% had detectable glyphosate in their urine on the day of application, with a maximum concentration of 29 ppb. All but one of the children with detectable concentrations had helped with the application or were present during herbicide mixing, loading, or application. None of the systemic doses estimated in this study approached the U.S. Environmental Protection Agency reference dose for glyphosate of 2 mg/kg/day. Nonetheless, it is advisable to minimize exposure to pesticides, and this study did identify specific practices that could be modified to reduce the potential for exposure. Key words: biomonitoring, epidemiologic studies, glyphosate, pesticide exposure. Environ Health Perspect 112:321-326 (2004). [Online 3 December 2003]

    Does pharmacotherapy for preterm labor sensitize the developing brain to environmental neurotoxicants? Cellular and synaptic effects of sequential exposure to terbutaline and chlorpyrifos in neonatal rats.

    Rhodes MC, Seidler FJ, Qiao D, Tate CA, Cousins MM, Slotkin TA.

    Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.

    It is increasingly clear that environmental toxicants target specific human subpopulations. In the current study, we examined the effects of prior developmental exposure to a beta(2)-adrenoceptor agonist used to arrest preterm labor, terbutaline, on the subsequent effects of exposure to the organophosphate insecticide, chlorpyrifos (CPF). Neonatal rats were given terbutaline on postnatal day (PN) 2-5, followed by CPF on PN11-14. Although neither treatment affected growth or viability, each elicited alterations in indices of brain cell differentiation and cholinergic innervation in the immediate posttreatment period (PN15), persisting into adulthood (PN60). Biomarkers of brain cell number (DNA concentration and content), cell size (protein/DNA ratio) and neuritic projections (membrane/total protein) were affected by either agent alone, with patterns consistent with neuronal and neuritic damage accompanied by reactive gliosis. The combined exposure augmented these effects by both additive and synergistic mechanisms. Similarly, choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, was affected only by combined exposure to both terbutaline and CPF. Indices of cholinergic synaptic activity [hemicholinium-3 and m(2)-muscarinic acetylcholine receptor binding] showed impairment after exposure to either terbutaline or CPF but the effects were more severe when the treatments were combined. These findings suggest that terbutaline, like CPF, is a developmental neurotoxicant, and that its use in the therapy of preterm labor may create a subpopulation that is sensitized to the adverse neural effects of a subsequent exposure to organophosphate insecticides.

    PMID: 14998686 [PubMed - indexed for MEDLINE]

    Integrated Pest Management in an Urban Community: A Successful Partnership for Prevention

    Barbara L. Brenner,1 Steven Markowitz,2 Maribel Rivera,1,3 Harry Romero,3 Matthew Weeks,4 Elizabeth Sanchez,3 Elena Deych,1 Anjali Garg,1 James Godbold,1 Mary S. Wolff,1 Philip J. Landrigan,1 and Gertrud Berkowitz1 1Department of Community and Preventive Medicine, Mount Sinai Medical Center, New York, New York, USA; 2Center for the Biology of Natural Systems, Queens College, City University of New York, New York, USA; 3Boriken Neighborhood Health Center, New York, New York; USA; 4Settlement Health, New York, New York, USA

    Abstract

    Pesticides, applied in large quantities in urban communities to control cockroaches, pose potential threats to health, especially to children, who have proportionately greater exposures and unique, developmentally determined vulnerabilities. Integrated pest management (IPM) relies on nonchemical tools--cleaning of food residues, removal of potential nutrients, and sealing cracks and crevices. Least toxic pesticides are used sparingly. To evaluate IPM's effectiveness, the Mount Sinai Children's Environmental Health and Disease Prevention Research Center, in partnership with two community health centers in East Harlem, New York City (NY, USA), undertook a prospective intervention trial. Families (n = 131) enrolled when mothers came to the centers for prenatal care. Household cockroach infestation was measured by glue traps at baseline and 6 months afterward. The intervention group received individually tailored IPM education, repairs, least-toxic pest control application, and supplies, with biweekly pest monitoring for 2 months and monthly for 4 months. The control group, residing in East Harlem and demographically and socioeconomically similar to the intervention group, received an injury prevention intervention. The proportion of intervention households with cockroaches declined significantly after 6 months (from 80.5 to 39.0%). Control group levels were essentially unchanged (from 78.1 to 81.3%). The cost, including repairs, of individually tailored IPM was equal to or lower than traditional chemically based pest control. These findings demonstrate that individually tailored IPM can be successful and cost-effective in an urban community. Key words: children's environmental health, cockroach, community intervention trial, integrated pest management, pesticides, urban built environment. Environ Health Perspect 111:1649-1653 (2003). [Online 2 July 2003]

    Risk factors for female infertility in an agricultural region

    Greenlee, AR, TE Arbuckle and P-H Chyou. 2003.
    Epidemiology 14:429-436

    Greenlee et al. report a strong association between using herbicides and infertility in women. In their study population, women who were infertile were 27 times more likely to have mixed or applied herbicides in the two years prior to attempting conception than women who were fertile. Other factors, including smoking and exposure to passive smoke, steady weight gain during adult life, and consuming alcoholic beverages were also associated with infertility.

    What did they do? Greenlee et al. conducted a retrospective case-control study examining the association between infertility in women and different risk factors.

    They recruited infertile women to the study via electronic records of women seeking infertility treatment. Their diagnoses included endometriosis, anovulation, pituitary-hypothalamic dysfunctions, etc. Couples whose sterility was a result of any form of male infertility or surgival intervention, e.g., hysterectomy or vasectomy, were excluded from the analysis.

    The controls were pregnant women from the same population. From the same age range, control women were seeking prenatal care during their first pregnancy, and had conceived in fewer than 12 months of trying. Any controls who reported ever having difficulty conceiving or maintaining a pregnancy, or whose male partner had a questionable history of infertility were also excluded.

    Controls were then matched to cases on the bases of age and date of clinical service.

    To determine exposure histories, cases and controls were interviewed about their activities for the 2 years prior to attempting to become pregnant. The questionnaire included questions on demographics, occupation, exposures, pesticide use, residency on a farm, tobacco and alcohol use, etc.

    What did they find? A total of 1,791 potential cases were screened for the study, along with 822 potential controls. After recruitment and screening, 322 cases and 322 matched controls participated in the study. Cases and controls were well matched for most variables, including age, household income, smoking status, body mass index, age at menarche, and number of sexual partners in lifetime.

    They differed somewhat in schooling (cases more likely to be a high school graduate; but not more likely to have schooling beyond high school). Cases were somewhat more likely to have exposure to passive smoke, to consume alcohol, and to have steadily gained weight. The odds-ratios for these variables were mostly under 2, with the odds-ratio of infertility rising to 6.7 for women who consumed at least 7 alcoholic drinks per week.

    Of several associations that Greenlee et al. examined between infertility and exposure to agricultural chemicals, two stood out: infertile women were almost 27 times more likely to have mixed or applied herbicides (but not insecticides) than fertile women, and 3.3 times more likely to have used fungicides. Both these odds-ratios reflect adjustments for maternal level of education, passive smoke exposure and other variables. Perhaps paradoxically, living on a farm, ranch or in a rural home reduced the likelihood of infertility.

    While the 27-fold increase in risk of infertility associated with having mixed or applied herbicides was very strong, the number of case women who fell in this category, 21, was relatively small. Hence the 95% confidence limits for the estimate of the odds-ratio was quite broad, from 1.9 to 348.

    What does it mean? These findings are consistent with a host of previous studies, both epidemiological research and laboratory experiments, that have found associations between infertility and agricultural chemicals. The laboratory experiments with animals and cell lines are unambiguous: an array of compounds working through multiple pathways affecting a variety of specific endpoints can suppress fertility in exposed animals. In people, elevated risk of poor sperm quality in Missouri men with relatively high urinary levels of alachlor, atrazine and diazinon, reported recently by Swan et al. in 2003, is the most powerful example to date.

    The collective weight of evidence is very strong, especially in light of the animal experiments. Taken together, they indicate that fertility of American women and men is being undermined by today's use of agricultural chemicals. Greenlee et al.'s data in this study suggest that precautionary measures to avoid impairing fertility should include avoiding working with herbicides and fungicides for at least two years prior to attempting to conceive. Swan's results, on the other hand, indicate that sufficient exposure to impair fertility can take place even without working directly with pesticides, and thus that broader measures to reduce exposures will be necessary.

    Cancer Risk and Parental Pesticide Application in Children of Agricultural Health Study Participants

    NIH-published journal, Environmental Health Perspectives

    Kori B. Flower, Jane A. Hoppin, Charles F. Lynch, Aaron Blair, Charles Knott, David L. Shore, and Dale P. Sandler

    Abstract

    Parental exposure to pesticides may contribute to childhood cancer risk. Through the Agricultural Health Study (AHS), a prospective study of pesticide applicators in Iowa and North Carolina, we examined childhood cancer risk and associations with parental pesticide application. Identifying information for 17,357 children of Iowa pesticide applicators was provided by parents via questionnaires (1993-1997) and matched against the Iowa Cancer Registry. Fifty incident childhood cancers were identified (1975-1998). Risk of all childhood cancers combined was increased (standardized incidence ratio (SIR)=1.36; 95% CI=1.03, 1.79). Risk of all lymphomas combined was also increased (SIR=2.18; 95% CI=113, 4.19), as was risk of Hodgkin's lymphoma (SIR=2.56; 95% CI=1.06, 6.14). Logistic regression was used to explore associations between self-reported parental pesticide application practices and childhood cancer risk. No association was detected between frequency of parental pesticide application and childhood cancer risk. An increased risk of cancer was detected among children whose fathers did not use chemically resistant gloves (OR=1.98; 95% CI=1.05, 3.76) compared with children whose fathers used gloves. Of sixteen specific pesticides used by fathers prenatally, ORs were increased for aldrin (OR=2.66), DDVP (OR= 2.06), and ETPC (OR=1.91). However, these results were based on small numbers and not supported by prior biologic evidence. Identification of excess lymphoma risk suggests that farm exposures including pesticides may play a role in the etiology of childhood lymphoma.

    Study Shows Neurotoxic Pesticide Chlorpyrifos (Dusban) Also Damages Heart and Liver

    (Beyond Pesticides, November 21, 2003) According to Science News, a new study has found chlorpyrifos, a neurotoxic organophosphate insecticide commonly sold as Dursban, was recently found to damage heart and liver cells, in addition to the affects it is already known to have on the brain. Although chlorpyrifos had many of its uses "phased-out" by an agreement between EPA and the pesticide industry in 2000, it may still be used on golf courses, in baits, in agriculture, for mosquito control and in food processing plants. Existing stocks purchased before 2002 may be used indefinitely.

    To test for effects of the chemical outside the nervous system, researchers at Duke University in Durham, N.C., injected rats daily with 1, 2, or 5 milligrams of chlorpyrifos per kilogram of body weight for 4 consecutive days. Some animals received the injections while they were pregnant, and their offspring were then studied for possible effects. Other animals were exposed during the first or second week of life. The researchers looked for effects shortly after exposure and when the animals were juveniles and adults.

    While the doses of chlorpyrifos were too low to cause immediate symptoms, rats exposed in utero or during the first week after birth later showed subtle biochemical abnormalities. Chlorpyrifos exposure in older animals seldom had an effect, suggesting that a "window of vulnerability" closes soon after birth, say Theodore Slotkin, PhD, and his colleagues at Duke.

    The abnormalities affect adenylyl cyclase signaling, a process by which cells communicate, and in some experiments, effects were evident only in male rats. Because adenylyl cyclase signaling modifies insulin production, glucose metabolism, and heart rate, the findings imply that early exposure to chlorpyrifos and other organophosphates could increase risks for cardiovascular and metabolic disorders that typically arise later in life, Dr. Slotkin argues.