# Presentation: 438026

## CHILDREN AND PESTICIDES:  INVESTIGATING EXPOSURE, SUSCEPTIBILITY, AND EFFECTS THROUGH EPIDEMIOLOGY

**CHILDREN AND PESTICIDES:  INVESTIGATING EXPOSURE, SUSCEPTIBILITY, AND EFFECTS THROUGH EPIDEMIOLOGY**
- Kacee Deener, Chris Saint, Nigel Fields
- U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Research

*** ******What is the basis for differential risk?***
***What is the risk to each subpopulation***

**Research Goals**

**Methods/Approach**

**Impact and Outcomes**

**Results/Conclusions**

**Future Directions**

**Science Questions**

-  Wide dissemination of research results to community groups, local health departments, and the scientific community
-  Collaborations between the academic community and EPA scientists
-  Demonstration of public health benefit resulting from a regulatory decision
-  Results have led to a re-evaluation of the some of the approaches used to set benchmark doses for estimating risk in regulatory programs
-  Results will likely inform the planning and implementation of the National Children’s Study

- The EPA-funded children’s environmental health research centers are ongoing.  Future efforts will continue to make important strides in the field of environmental epidemiology and children’s environmental health.

**References**

- USEPA, Office of Research and Development.  Human Health Research Strategy, September 2003.
- Whyatt, R.M., et al.  Prenatal Insecticide Exposures and Birth Weight and Length among an Urban Minority Cohort.  **Environmental Health Perspectives** 112(10): 1125-1132 (2004).
- Castorina, R., et al.  Cumulative Organophosphate Pesticide Exposure and Risk Assessment among Pregnant Women Living in an Agricultural Community:  A Case Study from the CHAMACOS Cohort.  **Environmental Health Perspectives** 111(13): 1640-1648 (2003).
- Chen, J., et al.  Increased Influence of Genetic Variation on PON1 Activity in Neonates.  **Environmental Health Perspectives** 111(11): 1403-1409 (2003).
- Berkowitz, G.S., et al.  In Utero Pesticide Exposure, Maternal Paraoxonase Activity, and Head Circumference.  Environmental Health Perspectives 112(3):  388-391 (2004).

- Evidence suggests that recent EPA restrictions on the use of certain OP pesticides in the home have reduced the exposure of mothers and infants to these pesticides, thereby impacting fetal growth.
- Findings indicate that certain populations, such as women living in agricultural areas, may be differentially exposed to higher levels of pesticides, resulting in dose estimates that exceed benchmarks developed by EPA for estimating risk..
- Discovery of an apparent gene-environment interaction for OP pesticide exposure and PON1 polymorphisms shows a genetic basis for differential risk.
- Substantially lower expression levels of PON1 in human infants than adults shows a basis for differential risk in human infants.

_**Factors Impacting Vulnerability**_
**Lifestage** - including specific windows of vulnerability (early gestation, throughout pregnancy, early childhood, adolescence)
**Genetic susceptibility** - (e.g., polymorphisms for metabolizing enzymes)
**Preexisting disease**
**Physical and social environment**
***There are many complex interactions among these risk factors that are best teased out through carefully designed epidemiological studies.***
- Since 1998, ORD has funded 13 children’s environmental health research centers that have developed multidisciplinary basic and applied research to support studies on the causes and mechanisms of children’s environmentally induced diseases, and to identify relevant environmental exposures of concern.  Several of these centers focus on pesticide exposure and health effects.

- Paraoxanase-1 (PON1) detoxifies organophosphates by cleavage of active oxons before they have a chance to inhibit cholinesterase.
- There are five polymorphisms in the PON1 gene.
- The five PON1 genotypes were determined for maternal blood (n=402) and cord blood (n=229)
- Compared with adults, neonates had lower PON1 activity, implying reduced capacity to detoxify organophosphates.
- There was a larger difference in activity between genotype groups in neonates than in adults.
- These studies also indicate that not only is the average potential risk to a fetus or newborn from organophosphate exposure greater than in the adult, the range of protection afforded by PON1 is more dependent on genotype than in the adult.

- Researchers investigated the relationship among prenatal pesticide exposure, PON1 polymorphisms and enzyme activity, and infant growth and neurodevelopment
- Prospective, multiethnic cohort study of mothers and infants delivered at Mount Sinai Hospital in New York City (n=404)
- Evaluated effects of pesticide exposure on birth weight, length, head circumference, and gestational age
- Neither questionnaire data nor pesticide metabolite levels were associated with growth indices or gestational age
- Maternal levels of chlorpyrifos above the level of detection coupled with low maternal PON1 activity were associated with a significant but small reduction in head circumference
- Small head size has been found to be predictive of subsequent cognitive ability
- Data suggest chlorpyrifos may have a detrimental effect on fetal neurodevelopment among mothers with low PON1 activity

-  Study cohort made up of women living in California’s Salinas Valley where approximately 230,000 kg of organophosphate (OP) pesticides are applied annually
-  Pregnant women were enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a longitudinal birth cohort (n=446)
-  Used 3 urine samples from each woman to estimate OP pesticide doses (using 2 methods)
-  Method 1 assumed the metabolites were attributable entirely to a single OP pesticide
-  Method 2 adopted USEPA’s draft guidelines for cumulative risk assessment to estimate dose from a mixture of OP pesticides that share a common mechanism of toxicity
-  Using Method 1, between 0% and 36.1% of study participants’ doses failed to attain a margin of exposure (MOE) of 100 relative to the EPA oral benchmark dose 10 (BMD10)
-  Using Method 2, 14.8% of the doses failed to attain an MOE of 100 relative to the BMD10 (point estimate could range from 1 to 34%)
- Based on dose estimates for a single OP pesticide (method 1), between 0% and 36.1% of study participants were within a  margin of exposure (MOE) of 100 relative to the U.S. EPA oral benchmark dose10 (BMD10).  Also the cumulative OP pesticide dose estimates (method 2) and found that 14.8% of the doses failed to attain an MOE of 100 relative to the BMD10

_**PON1 Genetic Susceptibility (Chen et al, 2003)**_

_**Gene-Environment Interaction (Berkowitz et al, 2004)**_

_**Differential exposure and vulnerability among pregnant women living in an agricultural community (Castorina et al, 2003)**_

_**Regulatory Actions Impact Health Outcomes (Whyatt et al, 2004)**_

- To understand why some people, or some groups of people, are more highly exposed to environmental toxicants than others;
- To understand why some people, or some groups of people, are more susceptible to the effects of exposure; and
- To understand the causes of environmentally induced diseases in children

- These findings indicate that certain populations, such as women living in agricultural areas, may be exposed to pesticide levels that result in dose estimates that exceed benchmarks based on doses expected to produce a 10% reduction in brain cholinesterase activity compared with background response in rats.

- Controlling for confounders, no association was found between maternal personal air insecticide levels and birth weight, length, or head circumference
- For each log unit increase in cord plasma chlorpyrifos levels, birth weight decreased by 42.6 g (p=0.03) and birth length decreased by 0.24 cm (p=0.04)
- Combined measures of (ln) cord plasma chlorpyrifos and diazinon were inversely associated with birth weight and length (p<0.05)
- Birth weight averaged 186.3 g less among newborns with the highest compared with the lowest exposure levels (p=0.01)
- Associations between birth weight and length and cord plasma chlorpyrifos and diazinon were highly significant (p<0.007) among newborns born before the 2000-2001 USEPA action to phase out residential use of these insecticides
- Among newborns born after January 2001, exposure levels were substantially lower, and no association with fetal growth was apparent (p>0.8).
- Results indicate that prenatal chlorpyrifos exposures have impaired fetal growth among this cohort and that diazinon exposures may have contributed to the effects
- Findings support recent regulatory action to phase out indoor residential uses of these insecticides

- Results are from an ongoing prospective cohort study of minority mothers and their newborns to evaluate the effects of prenatal exposures on birth outcomes and neurodevelopment.
- Questionnaire data, prenatal personal ambient air samples, blood samples, and measures of fetal growth were used to assess exposure and effect