Chlorpyrifos and Human Health

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Revised Human Health Risk Assessment on Chlorpyrifos - US Environmental Protection Agency (2017)

This assessment shows dietary and drinking water risks for the current uses of chlorpyrifos. Based on current labeled uses, the revised analysis indicates that expected residues of chlorpyrifos on food crops exceed the safety standard under the Federal Food, Drug, and Cosmetic Act (FFDCA). In addition, the majority of estimated drinking water exposure from currently registered uses, including water exposure from non-food uses, continues to exceed safe levels, even taking into account more refined drinking water exposure. This assessment also shows risks to workers who mix, load and apply chlorpyrifos pesticide products.
In March 2017, EPA denied a petition asking us to revoke all pesticide tolerances (maximum residue levels in food) for chlorpyrifos and cancel all chlorpyrifos registrations. We will continue to review the science addressing neurodevelopmental effects of chlorpyrifos as part of the ongoing registration review and complete our assessment by the statutory deadline of October 1, 2022.
This was one of the first risk assessments to employ a physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model. This is a mathematical model that enhances our ability to assess risk by allowing us to consider variations in a chemical’s effects on a person based on such variables as age and genetics and allows us to predict how the same dose may affect various members of a large population differently. EPA has held several meetings of the FIFRA Scientific Advisory Panel to get independent advice on the relevance and usefulness of a PBPK/PD model in assessing a chemical’s risks, including one meeting specifically on PBPK/PD and chlorpyrifos.
EPA has taken actions to help protect wildlife from chlorpyrifos exposure. For example, many of the reported incidents of wildlife mortality associated with chlorpyrifos use were related to residential lawn and termite uses and use on golf courses. The residential uses have been eliminated; termiticide uses have been restricted; and the application rate on golf courses has been reduced. Additionally, no-spray buffers around surface water bodies, as well as rate reductions for agricultural uses, further reduced the environmental burden of chlorpyrifos. The agency is currently consulting with the U.S. Fish and Wildlife Services and the National Marine Fisheries Services to evaluate potential impacts on endangered species.

Neurodevelopmental Disorders and Prenatal Residential Proximity to Agricultural Pesticides: The CHARGE Study - Shelton et al. (2014)

METHODS: The CHARGE study is a population-based case–control study of ASD, DD, and typical development. For 970 participants, commercial pesticide application data from the California Pesticide Use Report (1997–2008) were linked to the addresses during pregnancy. Pounds of active ingredient applied for organophophates, organochlorines, pyrethroids, and carbamates were aggregated within 1.25-km, 1.5-km, and 1.75-km buffer distances from the home. Multinomial logistic regression was used to estimate the odds ratio (OR) of exposure comparing confirmed cases of ASD (n = 486) or DD (n = 168) with typically developing referents (n = 316).
RESULTS: Approximately one-third of CHARGE study mothers lived, during pregnancy, within 1.5 km (just under 1 mile) of an agricultural pesticide application. Proximity to organophosphates at some point during gestation was associated with a 60% increased risk for ASD, higher for third-trimester exposures (OR = 2.0; 95% CI: 1.1, 3.6), and second-trimester chlorpyrifos applications (OR = 3.3; 95% CI: 1.5, 7.4). Children of mothers residing near pyrethroid insecticide applications just before conception or during third trimester were at greater risk for both ASD and DD, with ORs ranging from 1.7 to 2.3. Risk for DD was increased in those near carbamate applications, but no specific vulnerable period was identified.
CONCLUSION: This study of ASD strengthens the evidence linking neurodevelopmental disorders with gestational pesticide exposures, particularly organophosphates, and provides novel results of ASD and DD associations with, respectively, pyrethroids and carbamates.

Prenatal Residential Proximity to Agricultural Pesticide Use and IQ in 7-Year-Old Children - Gunier et al. (2016)

METHODS: Participants included mothers and children (n=283) living in the agricultural Salinas Valley of California enrolled in the Center for the Health Assessment of Mothers and Children Of Salinas (CHAMACOS) study. We estimated agricultural pesticide use within one km of maternal residences during pregnancy using a geographic information system, residential location, and California's comprehensive agricultural Pesticide Use Report data. We used regression models to evaluate prenatal residential proximity to agricultural use of five potentially neurotoxic pesticide groups (organophosphates, carbamates, pyrethroids, neonicotinoids, and manganese fungicides) and five individual organophosphates (acephate, chlorpyrifos, diazinon, malathion and oxydemeton-methyl) and cognition in 7-year old children. All models included prenatal urinary dialkyl phosphate metabolite concentrations.
RESULTS: We observed a decrease of 2.2 points (95% Confidence Interval (CI): -3.9, -0.5) in Full-Scale intelligence quotient (IQ) and 2.9 points (95% CI: -4.4, -1.3) in verbal comprehension for each standard deviation increase in toxicity-weighted use of organophosphate pesticides. In separate models, we observed similar decrements in Full-Scale IQ with each standard deviation increase of use for two organophosphates (acephate and oxydemeton-methyl) and three neurotoxic pesticide groups (pyrethroids, neonicotinoids, and manganese fungicides).
CONCLUSION: This study identified potential relationships between maternal residential proximity to agricultural use of neurotoxic pesticides and poorer neurodevelopment in children.

Chlorpyrifos and neurodevelopmental effects: a literature review and expert elicitation on research and policy (2012)


Most experts who responded to the first questionnaire felt that there was already enough evidence to support a ban on indoor uses of CPF in the EU. However, most felt additional research is still required in several areas. The responses from the first questionnaire were used to formulate the second questionnaire addressing the feasibility of government action. In turn, these expert participants were invited to attend a special session at the EuroTox congress in Dresden in 2009.


Some of the evidence that CPF contributes to neurodevelopmental disorders is still disputed among experts, and the overall sense is that further research and public awareness are warranted. There have been campaigns in North America making the potential exposure concerns known, but such information is not widely known in the EU. The ability of government action to produce change is strongly felt in some quarters while others believe better knowledge of consumer use trends would have a greater impact.

Review of the Toxicology of Chlorpyrifos With an Emphasis on Human Exposure and Neurodevelopment (2008)

ABSTRACT This review examines the large body of toxicological and epidemiological information on human exposures to chlorpyrifos, with an emphasis on the controversial potential for chlorpyrifos to induce neurodevelopmental effects at low doses.

The results of this review demonstrate that the use of urinary 3,5,6-trichlorpyridinol (TCPy), a metabolite of chlorpyrifos as a biomarker of nonoccupational exposure is problematic and may overestimate nonoccupational exposures to chlorpyrifos by 10-to 20-fold because of the widespread presence of both TCPy and chlorpyrifos-methyl in the food supply.

Current “background” (nonoccupational) levels of exposure to chlorpyrifos are several orders of magnitude lower than those required to inhibit plasma cholinesterase activity, which is a more sensitive target than nervous system cholinesterase.

However, several in vitro studies have identified putative neurodevelopmental mechanisms that are altered at concentrations of chlorpyrifos below those that inhibit cholinesterases. Although one human cohort study reported an association between maternal and cord blood chlorpyrifos levels and several measures of neurodevelopment, two other cohort studies that utilized urinary TCPy as a surrogate for chlorpyrifos exposure did not demonstrate an association.

Although the weight of the scientific evidence demonstrates that current levels of chlorpyrifos exposure will not have any adverse effects on neurodevelopment that might result from inhibition of nervous system cholinesterases, several recent studies propose alternative mechanisms.

Thus, further in vivo investigation on neurodevelopment in an appropriate animal model is needed; additional epidemiological studies may be warranted if a suitable, chlorpyrifos-exposed cohort can be identified and more rigorous measures of exposure are utilized.

Organophosphate Pesticide Exposure and Attention in Young Mexican-American Children: The CHAMACOS Study (2010)

BACKGROUND: Exposure to organophosphate (OP) pesticides, well‑known neurotoxicants, has been associated with neurobehavioral deficits in children.

OBJECTIVES: We investigated whether OP exposure, as measured by urinary dialkyl phosphate (DAP) metabolites in pregnant women and their children, was associated with attention‑related outcomes among Mexican‑American children living in an agricultural region of California.

METHODS: Children were assessed at ages 3.5 years (n = 331) and 5 years (n = 323). Mothers completed the Child Behavior Checklist (CBCL). We administered the NEPSY‑II visual attention sub‑test to children at 3.5 years and Conners’ Kiddie Continuous Performance Test (K‑CPT) at 5 years.

The K‑CPT yielded a standardized attention deficit/hyperactivity disorder (ADHD) Confidence Index score. Psychometricians scored behavior of the 5‑year‑olds during testing using the Hillside Behavior Rating Scale.

RESULTS: Prenatal DAPs (nanomoles per liter) were non-significantly associated with maternal report of attention problems and ADHD at age 3.5 years but were significantly related at age 5 years [CBCL attention problems: β = 0.7 points; 95% confidence interval (CI), 0.2–1.2; ADHD: β = 1.3; 95% CI, 0.4–2.1].

Prenatal DAPs were associated with scores on the K‑CPT ADHD Confidence Index > 70th percentile [odds ratio (OR) = 5.1; 95% CI, 1.7–15.7] and with a composite ADHD indicator of the various measures (OR = 3.5; 95% CI, 1.1–10.7). Some outcomes exhibited evidence of effect modification by sex, with associations found only among boys. There was also limited evidence of associations between child DAPs and attention.

CONCLUSIONS: In utero DAPs and, to a lesser extent, postnatal DAPs were associated adversely with attention as assessed by maternal report, psychometrician observation, and direct assessment. These associations were somewhat stronger at 5 years than at 3.5 years and were stronger in boys.


. . . We measured six DAP metabolites in maternal and child urine: a) three dimethyl phosphate (DM) metabolites (dimethylphosphate, dimethylthiophosphate, dimethyldithiophosphate), representing breakdown of O,O-dimethyl-substituted OP pesticides such as malathion, oxydemeton-methyl, and dimethoate, and b) three diethyl phosphate (DE) metabolites (diethylphosphate, diethylthiophosphate, and diethyldithiophosphate) derived from O,O-diethyl-substituted OP pesticides such as chlorpyrifos and diazinon.

These six metabolites cannot be traced back to individual pesticides but, taken together, represent the breakdown products of approximately 80% of the total OP pesticides used in the Salinas Valley. [PD]

Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First 3 Years of Life Among Inner-City Children (2006)

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.

Seven-Year Neurodevelopmental Scores and Prenatal Exposure to Chlorpyrifos, a Common Agricultural Pesticide (2011)

In a longitudinal birth cohort study of inner-city mothers and children (Columbia Center for Children’s Environmental Health), we have previously reported that prenatal exposure to chlorpyrifos (CPF) was associated with neurodevelopmental problems at 3 years of age.

Conclusions: We report evidence of deficits in Working Memory Index and Full-Scale IQ as a function of prenatal CPF exposure at 7 years of age. These findings are important in light of continued widespread use of CPF in agricultural settings and possible longer-term educational implications of early cognitive deficits.

Early-life Exposure to Organophosphate Pesticides and Pediatric Respiratory Symptoms in the CHAMACOS Cohort (2015)

BACKGROUND: Although pesticide use is widespread, the possible effect of early-life exposure to organophosphate (OP) on pediatric respiratory health is not well described.

OBJECTIVES: We investigated the relationship between early-life exposure to OPs and respiratory outcomes.

METHODS: Participants included 359 mothers and children from the CHAMACOS birth cohort. Dialkyl phosphate (DAP) metabolites of OP pesticides, specifically diethyl (DE) and dimethyl (DM) phosphate metabolites, were measured in urine from mothers twice during pregnancy (mean = 13 and 26 weeks gestation) and from children five times during childhood (0.5–5 years). Childhood DAP concentrations were estimated by the area under curve (AUC). Mothers reported their child’s respiratory symptoms at 5 and 7 years of age. We used generalized estimating equations (GEE) to examine associations of prenatal and childhood DAP concentrations with repeated measures of respiratory symptoms and exercise-induced coughing at 5 and 7 years of age, adjusting for child’s sex and age, maternal smoking during pregnancy, secondhand tobacco smoke, season of birth, PM2.5, breastfeeding, mold and cockroaches in home, and distance from highway.

RESULTS: Higher prenatal DAP concentrations, particularly DE, were nonsignificantly associated with respiratory symptoms in the previous 12 months at 5 or 7 years of age [adjusted odds ratio (aOR) per 10-fold increase = 1.44; 95% CI: 0.98, 2.12]. This association was strongest with total DAP and DE from the second half of pregnancy (aOR per 10-fold increase = 1.77; 95% CI: 1.06, 2.95; and 1.61; 95% CI: 1.08, 2.39, respectively). Childhood DAP, DE, and DM concentrations were associated with respiratory symptoms and exercise-induced coughing in the previous 12 months at 5 or 7 years of age (total DAPs: aOR per 10-fold increase = 2.53; 95% CI: 1.32, 4.86; and aOR = 5.40; 95% CI: 2.10, 13.91, respectively).

CONCLUSIONS: Early-life exposure to OP pesticides was associated with respiratory symptoms consistent with possible asthma in childhood.

. . . In animal studies, the OPs—chlorpyrifos, parathion, and diazinon—induced airway hyperreactivity at doses below those causing AChE inhibition


ABSTRACT A panel of toxicology and medical experts was convened on 7-9 April 1997 to consider the available scientific literature on chlorpyrifos, both published and unpublished, to determine the acute and chronic toxicology reference dose (RfD). In the course of reviewing this literature it became apparent that there was a large body of literature on human exposures to chlorpyrifos, as well as chlorpyrifos and/or other organophosphates. This literature, although not useful for determining the RfD for chlorpyrifos, needed to be analyzed for potential critical human effects resulting from either acute or prolonged chlorpyrifos exposures, or inferred from exposures to other organophosphates. The expert panel proceeded to review these data also, and the evaluations and discussions of these studies are contained in this report of the proceedings.

The expert panel concluded that for acute poisonings there was no clear evidence for long-term effects from organophosphates, other than finding cases of organophosphorus-induced delayed neurotoxicity (OPIDN) from suicidal ingestion. In animal experimental data (mainly from studies on nerve gases), seizures during acute poisoning by organophosphates occur, resulting in morphological damage. Neurobehavioral effects observed are the result of the seizures. The panel agreed that long-term exposure to organophosphate compounds does not cause problems in the peripheral or central nervous system, unless poisoning is acute and severe.

With respect to neurobehavioral effects, manifestations of clinical neurobehavioral effects are unlikely. All of the available evidence shows that disturbances do not occur unless cholinesterase inhibition has been clearly exhibited. The review of these papers was considered to be of interest in allaying some of the potential concerns regarding long-term effects of organophosphate pesticides, including chlorpyrifos.

Brain anomalies in children exposed prenatally to a common organophosphate pesticide (2012)

ABSTRACT Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9–11.2 y, selected from a nonclinical, representative community-based cohort.

Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere.

Group differences were derived from exposure effects on underlying white matter. A significant exposure × IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose–response relationship between CPF and cortical thickness.

This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain.

Prenatal Exposure to Organophosphate Pesticides and IQ in 7-Year-Old Children (2011)

Context: Organophosphate (OP) pesticides are neurotoxic at high doses. Few studies have examined whether chronic exposure at lower levels could adversely affect children’s cognitive development. Objective: We examined associations between prenatal and postnatal exposure to OP pesticides and cognitive abilities in school-age children.

Methods: We conducted a birth cohort study (Center for the Health Assessment of Mothers and Children of Salinas study) among predominantly Latino farmworker families from an agricultural community in California. We assessed exposure to OP pesticides by measuring dialkyl phosphate (DAP) metabolites in urine collected during pregnancy and from children at 6 months and 1, 2, 3.5, and 5 years of age. We administered the Wechsler Intelligence Scale for Children, 4th edition, to 329 children 7 years of age. Analyses were adjusted for maternal education and intelligence, Home Observation for Measurement of the Environment score, and language of cognitive assessment. Results: Urinary DAP concentrations measured during the first and second half of pregnancy had similar relations to cognitive scores, so we used the average of concentrations measured during pregnancy in further analyses. Averaged maternal DAP concentrations were associated with poorer scores for Working Memory, Processing Speed, Verbal Comprehension, Perceptual Reasoning, and Full-Scale intelligence quotient (IQ). Children in the highest quintile of maternal DAP concentrations had an average deficit of 7.0 IQ points compared with those in the lowest quintile. However, children’s urinary DAP concentrations were not consistently associated with cognitive scores.

Conclusions: Prenatal but not postnatal urinary DAP concentrations were associated with poorer intellectual development in 7-year-old children. Maternal urinary DAP concentrations in the present study were higher but nonetheless within the range of levels measured in the general U.S. population.

Biomarkers in assessing residential insecticide exposures during pregnancy and effects on fetal growth. (2005)

ABSTRACT The Columbia Center for Children's Environmental Health is using a combination of environmental and biologic measures to evaluate the effects of prenatal insecticide exposures among urban minorities in New York City. Of the 571 women enrolled, 85% report using some form of pest control during pregnancy and 46% report using exterminators, can sprays, and/or pest bombs.

Chlorpyrifos, diazinon, and propoxur were detected in 99.7-100% of 48-h personal air samples collected from the mothers during pregnancy (n = 394) and in 39-70% of blood samples collected from the mothers (n = 326) and/or newborns (n = 341) at delivery. Maternal and newborn blood levels are similar and highly correlated (r = 0.4-08, P < 0.001). Levels of insecticides in blood samples and/or personal air samples decreased significantly following the 2000-2001 U.S. Environmental Protection Agency's regulatory actions to phase out residential use of chlorpyrifos and diazinon. Among infants born prior to 1/1/01, birth weight decreased by 67.3 g (95% confidence interval (CI) -116.6 to -17.8, P = 0.008) and birth length decreased by 0.43 centimeters (95% CI, -0.73 to -0.14, P = 0.004) for each unit increase in log-transformed cord plasma chlorpyrifos levels.

Combined measures of (ln)cord plasma chlorpyrifos and diazinon (adjusted for relative potency) were also inversely associated with birth weight and length (P </= 0.007). Birth weight averaged 215.1 g less (95% CI -384.7 to -45.5) among those with the highest exposures compared to those without detectable levels. No association was seen between birth weight and length and cord plasma chlorpyrifos or diazinon among newborns born after 1/1/01 (P > 0.8).

Results support recent regulatory action to phase out residential uses of these insecticides.

Organophosphate Pesticide Exposure and Neurodevelopment in Young Shanghai Children (2012)

We investigated both the urinary levels of OP metabolites in children and their relationship with child neurodevelopment. Participating 301 young children (23–25 months of age) were recruited from two community hospitals in Shanghai between February and October 2008. 

We measured five nonspecific dialkyl phosphate (DAP) metabolite levels of OPs in the children’s urine and examined their association with the children’s developmental quotients (DQs) based on the Gesell Developmental Schedules (GDS). The creatinine-adjusted geometric means (GMs) of OP metabolites in urine samples were 11.27 μg/g for DMP; 6.99 μg/g for DMTP; 7.96 μg/g for DEP; 14.19 μg/g for DETP; and 4.55 μg/g for DEDTP. T

he children had relatively higher levels of OP urinary metabolites compared with those reported in developed countries, no association was found between child urinary levels of OP metabolites and any of the DQ scores. However, our results should be interpreted with caution, and more studies of children living in China are warranted given the relatively high levels of child OP urinary metabolites in Shanghai.

Urinary Metabolites of Organophosphate and Pyrethroid Pesticides and Behavioral Problems in Canadian Children (2103)

Objective: We examined the association between exposure to organophosphate and pyrethroid pesticides, indicated by urinary metabolites, and parentally reported behavioral problems in children.

Methods: We used data on children 6–11 years of age from the Canadian Health Measures Survey (2007–2009). We used logistic regressions to estimate odds ratios (ORs) for high scores on the Strengths and Difficulties Questionnaire (SDQ), which may indicate behavioral problems, in association with concentrations of pyrethroid and organophosphate metabolites in the urine of 779 children, adjusting for covariates (sex, age, race/ethnicity, income, parental education, blood lead levels, maternal smoking during pregnancy, and others).

Results: At least one urinary metabolite for organophosphates was detected in 91% of children, and for pyrethroids in 97% of children. Organophosphate metabolites were not significantly associated with high SDQ scores. The pyrethroid metabolite cis-DCCA [3-(2,2-dichlorovinyl)-2,2-dimethylycycl​opropanecarboxylic acid] was significantly associated with high scores for total difficulties on the SDQ (OR for a 10-fold increase = 2.0; 95% CI: 1.1, 3.6), and there was a nonsignificant association with trans-DCCA (OR = 1.6; 95% CI: 0.9, 3.0).

Conclusion: In contrast with previous studies, we did not observe an association between exposure to organophosphate pesticides and behavioral scores in children. However, some pyrethroid urinary metabolites were associated with a high level of parent-reported behavioral problems. Longitudinal studies should be conducted on the potential risks of pyrethroids.

SEE ALSO: FACTCHECK on Chlorpyrifos