Maryland Pesticide Network

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

Back to Top

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. More... [related stories] http://pediatrics.aappublications.org/cgi/content/abstract/peds.2006-0338v1?papetoc

Back to Top

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

Back to Top

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

Chaitali Sinha^a, Kavita Seth^a, Fakhrul Islam^b, Rajnish Kumar Chaturvedi^a, Shubha Shukla^a, Neeraj Mathur^c, N. Srivastava^a and Ashok Kumar Agrawal<sup>a, ,

a</sup>Developmental 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.

	This Document Abstract Full Text + Links PDF (385 K) Actions E-mail Article Neurotoxicology and Teratology Volume 28, Issue 4 , July-August 2006, Pages 472-481 Back to Top

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.

Back to Top

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.

Back to Top

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

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

Back to Top

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.

Back to Top

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).

Back to Top

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

Back to Top

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.

Back to Top

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.

Back to Top

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 Colborn^1,2

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.

References

Aldridge JE, Levin ED, Seidler FJ, Slotkin TA. 2005a. Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression. Environ Health Perspect 113:527-531.

Aldridge JE, Meyer A, Seidler FJ, Slotkin TA. 2005b. Alterations in central nervous system serotonergic and dopaminergic synaptic activity in adulthood after prenatal or neonatal chlorpyrifos exposure. Environ Health Perpect 113:1027-1031.

Aldridge JE, Seidler FJ, Meyer A, Thillai I, Slotkin TA. 2003. Serotonergic systems targeted by developmental exposure to chlorpyrifos: effects during different critical periods. Environ Health Perspect 111:1736-1743.

Aldridge JE, Seidler FJ, Slotkin TA. 2004. Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling. Environ Health Perspect 112:148-155.

Arbuckle TE, Schrader SM, Cole D, Hall JC, Bancej CM, Turner LA, et al. 1999. 2,4-Dichlorophenoxyacetic acid residues in semen of Ontario farmers. Reprod Toxicol 13:421-429.

Aspelin AL, Grube AH. 1999. Pesticides Industry Sales and Usage: 1996 and 1997 Market Estimates. EPA-733-R-99-001. Washington, DC:Biological and Economics Analysis Division, Office of Pesticide Programs, U.S. Environmental Protection Agency.

ATSDR. 2002. Toxicological Profile for Methoxychlor (Update). Atlanta, GA:Agency for Toxic Substances and Disease Registry.

Barone S Jr, Das KP, Lassiter TL, White LD. 2000. Vulnerable processes of nervous system development: a review of markers and methods. Neurotoxicology 21:15-36.

Berkowitz GS, Wetmur JG, Birman-Deych E, Obel J, Lapinski RH, Godbold JH, et al. 2004. In utero pesticide exposure, maternal paraoxonase activity, and head circumference. Environ Health Perspect 112:388-391.

Bortolozzi AA, Duffard RO, Evangelista de Duffard AM. 1999. Behavioral alterations induced in rats by a pre- and post-natal exposure to 2,4-dichlorophenoxyacetic acid. Neurotoxicol Teratol 21(4):451-465.

Bortolozzi A, Evangelista de Duffard AM, Dajas F, Duffard R, Silveira R. 2001. Intracerebral administration of 2,4-dichlorophenoxyacetic acid induces behavioral and neurochemical alterations in the rat brain. Neurotoxicology 22:221-232.

Bowers WJ, Nakai JS, Chu I, Wade MG, Moir D, Yagminas A, et al. 2004. Early developmental neurotoxicity of a PCB/organochlorine mixture in rodents after gestational and lactational exposure. Toxicol Sci 77:51-62.

Bradman A, Barr DB, Henn BGC, Drumheller T, Curry C, Eskenazi B. 2003. Measurement of pesticides and other toxicants in amniotic fluid as a potential biomarker of prenatal exposure: a validation study. Environ Health Perspect 111:1779-1782.

Brucker-Davis F. 1998. Effects of environmental synthetic chemicals on thyroid function. Thyroid 8:827-856.

Cassidy RA, Vorhees CV, Minnema DJ, Hastings L. 1994. The effects of chlordane exposure during pre- and postnatal periods at environmentally relevant levels on sex steroid-mediated behaviors and functions in the rat. Toxicol Appl Pharmacol 126:326-337.

Castro VL, Bernardi MM, Palermo-Neto J. 1992. Evaluation of prenatal aldrin intoxication in rats. Arch Toxicol 66:149-152.

CDC. 2001. National Report on Human Exposure to Environmental Chemicals. Atlanta, GA:Centers for Disease Control and Prevention.

CDC. 2003. Second National Report on Human Exposure to Environmental Chemicals. NCEH Publication no. 02-0716. Atlanta, GA:Centers for Disease Control and Prevention. Available: http://www.cdc.gov/exposurereport [accessed 12 December 2004].

Colbert NKW, Pelletier NC, Cote JM, Concannon JB, Jurdak NA, Minott SB, et al. 2005. Perinatal exposure to low levels of the environmental antiandrogen vinclozolin alters sex-differentiated social play and sexual behaviors in the rat. Environ Health Perspect 113:700-707.

Coronado GD, Thompson B, Strong L, Griffith WC, Islas I. 2004. Agricultural task and exposure to organophosphate pesticides among farmworkers. Environ Health Perspect 112:142-147.

Crumpton TL, Seidler FJ, Slotkin TA. 2000. Developmental neurotoxicity of chlorpyrifos in vivo and in vitro: effects on nuclear transcription factors involved in cell replication and differentiation. Brain Res 857:87-98.

Curl CL, Fenske RA, Elgethun K. 2003. Organophosphorus pesticide exposure of urban and suburban preschool children with organic and conventional diets. Environ Health Perspect 111:377-382.

Dam K, Seidler FJ, Slotkin TA. 1999. Chlorpyrifos releases nor-epinephrine from adult and neonatal rat brain synaptosomes. Brain Res Dev Brain Res 118:129-133.

Davidson PW, Weiss B, Myers GJ, Cory-Slechta DA, Brockel BJ, Young EC, et al. 2000. Evaluation of techniques for assessing neurobehavioral development in children. Neurotoxicology 21:957-972.

Dorea JG, Cruz-Granja AC, Lacayo-Romero ML, Cuadra-Leal J. 2001. Perinatal metabolism of dichlorodiphenyldichloro-ethylene in Nicaraguan mothers. Environ Res 86:229-237.

Duffard R, Garcia G, Rosso S, Bortolozzi A, Madariaga M, Di Paolo O, et al. 1996. Central nervous system myelin deficit in rats exposed to 2,4-dichlorophenoxyacteic acid throughout lactation. Neurotoxicol Teratol 18:691-696.

Eriksson P. 1997. Developmental neurotoxicity of environmental agents in the neonate. Neurotoxicology 18:719-726.

Eriksson P, Talts U. 2000. Neonatal exposure to neurotoxic pesticides increases adult susceptibility: a review of current findings. Neurotoxicology 21:37-47.

Evangelista de Duffard AM, Bortolozzi A, Duffard RO. 1995. Altered behavioral responses in 2,4-dichlorophenoxyacetic acid treated and amphetamine challenged rats. Neurotoxicology 16:479-488.

Evangelista de Duffard AM, de Alderete MN, Duffard R. 1990. Changes in brain serotonin and 5-hydroxyindolacetic acid levels induced by 2,4-dichlorophenoxyacetic butyl ester. Toxicology 64:265-270.

Foster W, Chan S, Platt L, Hughes C. 2000. Detection of endocrine disrupting chemicals in samples of second trimester human amniotic fluid. J Clin Endocrinol Metab 85:2954-2957.

Garcia G, Tagliaferro P, Bortolozzi A, Madariaga MJ, Brusco A, Evangelista de Duffard AM, et al. 2001. Morphological study of 5-HT neurons and astroglial cells on brain of adult rats perinatal or chronically exposed to 2,4-dichlorophenoxy acetic acid. Neurotoxicology 22:733-741.

Garcia SJ, Seidler FJ, Crumpton TL, Slotkin TA. 2001. Does the developmental neurotoxicity of chlorpyrifos involve glial targets? Macromolecule synthesis, adenylyl cyclase signaling, nuclear transcription factors, and formation of reactive oxygen in C6 glioma cells. Brain Res 891:54-68.

Garcia SJ, Seidler FJ, Qiao D, Slotkin TA. 2002. Chlorpyrifos targets developing glia: effects on glial fibrillary acidic protein. Brain Res Dev Brain Res 133:151-161.

Garry VF, Harkins ME, Erickson LL, Long-Simpson LK, Holland SE, Burroughs BL. 2002. Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA. Environ Health Perspect 110(suppl 3):441-449.

Gray LE Jr, Ostby J. 1998. Effects of pesticides and toxic substances on behavioral and morphological reproductive development: endocrine versus nonendocrine mechanisms. Toxicol Ind Health 14:159-184.

Gray LE Jr, Ostby JS, Kelce WR. 1994. Developmental effects of an environmental antiandrogen--the fungicide vinclozolin alters sex differentiation of the male rat. Toxicol Appl Pharmacol 129:46-52.

Hill RH Jr, Head SL, Baker S, Gregg M, Shealy DB, Bailey SL, et al. 1995. Pesticide residues in urine of adults living in the United States: reference range concentrations. Environ Res 71:99-108.

Hotchkiss AK, Ostby JS, Vandenbergh JG, Gray LE Jr. 2002. Androgens and environmental antiandrogens affect reproductive development and play behavior in the Sprague-Dawley rat. Environ Health Perspect 110(suppl 3):435-439.

Icenogle LM, Christopher NC, Blackwelder WP, Caldwell DP, Qiao D, Seidler FJ, et al. 2004. Behavioral alterations in adolescent and adult rats caused by a brief subtoxic exposure to chlorpyrifos during neurulation. Neurotoxicol Teratol 26:95-101.

Jarrell JF, Villeneuve D, Franklin C, Bartlett S, Wrixon W, Kohut J, et al. 1993. Contamination of human ovariam follicular fluid and serum by chlorinated organic compounds in three Canadian cities. Can Med Assoc J 148:1321-1327.

Johansson U, Fredriksson A, Eriksson P. 1995. Bioallethrin causes permanant changes in behavioral and muscarinic acetylcholine receptor variables in adult mice exposed neonatally to DDT. Eur J Pharmacol Environ Toxicol Pharmacol 293:159-166.

Johansson U, Fredriksson A, Eriksson P. 1996. Low-dose effects of paraoxon in adult mice exposed neonatally to DDT: changes in behavioural and cholinergic receptor variables. Environ Toxicol Pharmacol 2:307-314.

Kiely T, Donaldson D, Grube A. 2004. Pesticides Industry Sales and Usage: 2000 and 2001 Market Estimates. EPA-733-R-04-001. Washington, DC:Office of Pesticide Programs, U.S. Environmental Protection Agency.

Lakshmana MK, Raju TR. 1994. Endosulfan induces small but significant changes in the levels of noradrenaline, dopamine and serotonin in the developing rat brain and deficits in the operant learning performance. Toxicology 91:139-150.

Lamberson CK, Shavlik LJ, Scalzitti JM. 2001. Gestational eco-estrogen administration alters serotonin-2A, D1 and D2 dopamine receptor-mediated behaviors in pups. Soc Neurosci Abstr 27:1831.

Lassiter TL, Padilla S, Mortensen SR, Chanda SM, Moser VC, Barone S Jr. 1998. Gestational exposure to chlorpyrifos: apparent protection of the fetus? Toxicol Appl Pharmacol 152:56-65.

Levin ED, Addy N, Baruah A, Elias A, Christopher NC, Seidler FJ, et al. 2002. Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations. Neurotoxicol Teratol 24:733-741.

Makris S, Raffaele K, Sette W, Seed J. 1998. A retrospective analysis of twelve developmental neurotoxicity studies submitted to the US EPA Office of Prevention, Pesticides, and Toxic Substances. Washington, DC:U.S. Environmental Protection Agency.

MeisterPRO. 2004. Crop Protection Handbook. Willoughby, OH:Meister Publishing Co.

Meyer A, Seidler FJ, Aldridge JE, Tate CA, Cousins MM, Slotkin TA. 2004a. Critical periods for chlorpyrifos-induced developmental neurotoxicity: alterations in adenylyl cyclase signaling in adult rat brain regions after gestational or neonatal exposure. Environ Health Perspect 112:295-301.

Meyer A, Seidler FJ, Cousins MM, Slotkin TA. 2003. Developmental neurotoxicity elicited by gestational exposure to chlorpyrifos: When is adenylyl cyclase a target? Environ Health Perspect 111:1871-1876.

Meyer A, Seidler FJ, Slotkin TA. 2004b. Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling. Environ Health Perspect 112:170-178.

National Agricultural Statistics Service. 2005. NASS Pesticide Use Data. Available: http://old.ipmcenters.org/data-sources/nass/ [accessed 8 July 2005].

Ostrea EM Jr, Morales V, Ngoumgna E, Prescilla R, Tan E, Hernandez E, et al. 2002. Prevalence of fetal exposure to environmental toxins as determined by meconium analysis. Neurotoxicology 23:329-339.

Palanza P, Morellini F, Parmigiani S, vom Saal FS. 1999. Prenatal exposure to endocrine disrupting chemicals: effects on behavioral development. Neurosci Biobehav Rev 23:1011-1027.

Palanza P, Morellini F, Parmigiani S, vom Saal FS. 2002. Ethological methods to study the effects of maternal exposure to estrogenic endocrine disrupters--a study with methoxychlor. Neurotoxicol Teratol 24:55-69.

Pope CN, Chakraborti TK. 1992. Dose-related inhibition of brain and plasma cholinesterase in neonatal and adult rats following sublethal organophosphate exposures. Toxicology 73:35-43.

Pope CN, Chakraborti TK, Chapman ML, Farrar JD. 1992. Long-term neurochemical and behavioral effects induced by acute chlorpyrifos treatment. Pharmacol Biochem Behav 42:251-256.

Pope CN, Chakraborti TK, Chapman ML, Farrar JD, Arthun D. 1991. Comparison of in vivo cholinesterase inhibition in neonatal and adult rats by three organophosphorothioate insecticides. Toxicology 68:51-61.

Qiao D, Seidler FJ, Abreu-Villaca Y, Tate CA, Cousins MM, Slotkin TA. 2004. Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood. Brain Res Dev Brain Res 148(1):43-52.

Qiao D, Seidler FJ, Padilla S, Slotkin TA. 2002. Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period? Environ Health Perspect 110:1097-1103.

Qiao D, Seidler FJ, Slotkin TA. 2001. Developmental neuro-toxicity of chlorpyrifos modeled in vitro: comparative effects of metabolites and other cholinesterase inhibitors on DNA synthesis in PC12 and C6 cells. Environ Health Perspect 109:909-913.

Qiao D, Seidler FJ, Tate CA, Cousins MM, Slotkin TA. 2003. Fetal chlorpyrifos exposure: adverse effects on brain cell development and cholinergic biomarkers emerge postnatally and continue into adolescence and adulthood. Environ Health Perspect 111:536-544.

Rosso SB, Garcia GB, Madariaga MJ, Evangelista de Duffard AM, Duffard RO. 2000. 2,4-Dichlorophenoxyacetic acid in developing rats alters behaviour, myelination and regions brain gangliosides pattern. Neurotoxicology 21:155-163.

Roy TS, Andrews JE, Seidler FJ, Slotkin TA. 1998. Chlorpyrifos elicits mitotic abnormalities and apoptosis in neuro-epithelium of cultured rat embryos. Teratology 58:62-68.

Roy TS, Seidler FJ, Slotkin TA. 2004. Morphologic effects of subtoxic neonatal chlorpyrifos exposure in developing rat brain: regionally selective alterations in neurons and glia. Brain Res Dev Brain Res 148:197-206.

Santos HR, Cintra WM, Aracava Y, Maciel CM, Castro NG, Albuquerque EX. 2004. Spine density and dendritic branching pattern of hippocampal CA1 pyramidal neurons in neonatal rats chronically exposed to the organophosphate paraoxon. Neurotoxicology 25:481-494.

Saxena MC, Siddiqui MKJ, Agarwal V, Kuuty D. 1983. A comparison of organochlorine insecticide contents in specimens of maternal blood, placenta, and umbilical-cord blood from stillborn and live-born cases. J Toxicol Environ Health 11:71-79.

Schinas V, Leotsinidis M, Alexopoulos A, Tsapanos V, Kondakis XG. 2000. Organochlorine pesticide residues in human breast milk from southwest Greece: associations with weekly food consumption patterns of mothers. Arch Environ Health 55:411-417.

Schuh RA, Lein PJ, Beckles RA, Jett DA. 2002. Noncholinesterase mechanisms of chlorpyrifos neurotoxicity: altered phosphorylation of Ca2+/cAMP response element binding protein in cultured neurons. Toxicol Appl Pharmacol 182:176-185.

Siddiqui MKJ, Srivastava S, Srivastava SP, Mehrotra PK, Mathur N, Tandon I. 2003. Persistent chlorinated pesticides and intra-uterine foetal growth retardation: a possible association. Int Arch Occup Environ Health 76:75-80.

Simonetti J, Berner J, Williams K. 2001. Effects of p,p′-DDE on immature cells in culture at concentrations relevant to the Alaskan environment. Toxicol In Vitro 15:169-179.

Slotkin TA. 1999. Developmental cholinotoxicants: nicotine and chlorpyrifos. Environ Health Perspect 107(suppl 1):71-80.

Slotkin TA. 2004. Guidelines for developmental neurotoxicity and their impact on organophosphate pesticides: a personal view from an academic perspective. Neurotoxicology 25(4):631-640. [CrossRef].

Slotkin TA, Cousins MM, Tate CA, Seidler FJ. 2001. Persistent cholinergic presynaptic deficits after neonatal chlorpyrifos exposure. Brain Res 902:229-243.

Smith D. 1999. Worldwide trends in DDT levels in human breast milk. Int J Epidemiol 28(2):179-188. [CrossRef].

Sturtz N, Evangelista de Duffard AM, Duffard R. 2000. Detection of 2,4-dichlorophenoxyacetic acid (2,4-D) residues in neonates breast-fed by 2,4-D exposed dams. Neurotoxicology 21:147-154.

Swan SH, Kruse RL, Liu F, Barr DB, Drobnis EZ, Redmon JB, et al. 2003. Semen quality in relation to biomarkers of pesticide exposure. Environ Health Perspect 111:1478-1484.

vom Saal FS, Palanza P, Colborn T, Parmigiani S. 2003. Exposure to very low doses of endocrine disrupting chemicals (EDCs) during fetal life permanently alters brain development and behavior in animals and humans. In: Proceedings of Conference: International Seminar on Nuclear War and Planetary Emergencies, 27th Session, August 2002, Erice, Sicily (Ragaini RC, ed). Singapore:World Scientific Publishers, 293-308.

Whyatt RM, Barr DB. 2001. Measurement of organophosphate metabolites in postpartum meconium as a potential bio-marker of prenatal exposure: a validation study. Environ Health Perspect 109:417-420.

Young JG, Eskenazi B, Gladstone EA, Bradman A, Pedersen L, Johnson C, et al. 2005. Association between in utero organophosphate pesticide exposure and abnormal reflexes in neonates. Neurotoxicology 26(2):199-209.

Zheng Q, Olivier K, Won YK, Pope CN. 2000. Comparative cholinergic neurotoxicity of oral chlorpyrifos exposures in preweanling and adult rats. Toxicol Sci 55:124-132.

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.

View this table:
[in this window]
[in a new window]
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).

View this table:
[in this window]
[in a new window]
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.

View this table:
[in this window]
[in a new window]
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

1. Clavel J, Goubin A, Auclerc MF, et al. Incidence of childhood leukaemia and non-Hodgkin’s lymphoma in France: National Registry of Childhood Leukaemia and Lymphoma, 1990–1999. Eur J Cancer Prev 2004;13:97–103.[CrossRef][Medline]

2. Buckley JD, Robison LL, Swotinsky R, et al. Occupational exposures of parents of children with acute nonlymphocytic leukaemia: a report from the Childrens Cancer Study Group. Cancer Res 1989;49:4030–7.[Abstract]

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]

5. Lowengart RA, Peters JM, Cicioni C, et al. Childhood leukaemia and parents’ occupational and home exposures. J Natl Cancer Inst 1987;79:39–46.[Medline]

6. Ma X, Buffler PA, Gunier RB, et al. Critical windows of exposure to household pesticides and risk of childhood leukaemia. Environ Health Perspect 2002;110:955–60.[Medline]

7. Meinert R, Kaatsch P, Kaletsch U, et al. Childhood leukaemia and exposure to pesticides: results of a case-control study in northern Germany. Eur J Cancer 1996;32A:1943–8.[CrossRef]

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.

Back to Top

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

Back to Top

"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)

Back to Top

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

Back to Top

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]

Back to Top

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

Back to Top

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]

Back to Top

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.

Back to Top

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

• To determine whether a single class of product was responsible for the observed effect, the Total Chemical Burden score was recalculated 11 times by sequential removal of each individual product category followed by repeat analysis of the score containing the remaining 10 products. In all cases, there was no significant change in effect sizes suggesting that no single product was implicated.
• It was not possible to analyse the individual chemical agents in these data, as many products contain more than one class of chemical.
• Over the past two decades, consumption of household cleaning products has risen dramatically in the UK. Since 1994, according to the Office for National Statistics, expenditure on household cleaning materials (other than soap) has increased by 60% in real terms (fixed 1995 prices).
• ALSPAC The Avon Longitudinal Study of Parents and Children (also known as Children of the 90s) is a unique ongoing research project based in the University of Bristol. It enrolled 14,000 mothers during pregnancy in 1991-2 and has followed most of the children and parents in minute detail ever since.
• The ALSPAC study could not have been undertaken without the continuing financial support of the Medical Research Council, the Wellcome Trust, and the University of Bristol among many others.

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

Back to Top

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 (p_trend = 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]

Back to Top

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 Bleeke^1
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]

Back to Top

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]

Back to Top

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]

Back to Top

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.

Back to Top

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.

Back to Top

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.

Back to Top