# Exposures 

# of

# Children to 

# Organophosphate Pesticides andTheir Potential Adverse Health 

# Effects

Brenda 

### Eskenazi, Asa 

### Bradman, and 

### Rosemary Castorina

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

Recent studies show that young children can be exposed to pesticides during normal oral exploration of their environment and their level of dermal contact with floors and other surfaces. Children living in agricultural areas may be exposed to higher pesticide levels than other children because of pesticides tracked into their homes by household 

### members, by pesticide drift, by breast milk from their farmworker mother, orbyplaying in nearbyfields. Nevertheless, few studies have assessed the extent of children's pesticide exposure, and no studies have examined whether there are adverse health effects of chronic exposure. There is substantial toxicologic evidence that repeated low-level exposure to organophosphate 

### (OP) pesticides mayaffect neurodevelopment and growth in developing animals. For example, animal studies have reported neurobehavorial effects such as impairment on maze 

### performance, locomotion, and balance in neonates exposed in utero and during early postnatal life. Possible mechanisms for these effects include inhibition of brain acetylcholinesterase, downregulation of muscarinic receptors, decreased brain DNA synthesis, and reduced brain weight in 

### offspring. Research 

### findings also suggest that it is 

### biologically plausible that OP exposure may be related to respiratory disease in children through dysregulation of the autonomic nervous system. The University of California Berkeley Center for Children's Environmental Health Research is working to build a community-university partnership to study the environmental health of rural children. This Center for the Health Assessment of Mothers and Children of Salinas, or CHAMACOS in Monterey County, California, will assess in utero and postnatal OP pesticide exposure and the relationship of exposure to neurodevelopment, growth, and symptoms of respiratory illness in children. The ultimate goal of the center is to translate research 

### findings into a reduction of children's exposure to pesticides and other environmental agents, and thereby reduce the incidence of environmentally related disease. Keywords: asthma, children, environment, exposure, growth, neurodevelopment, organophosphate, pesticide.

- Environ Health 

### Perspect 1

### 07(suppl 3):409-419 

### (1999). 

### http.//ehpnetl.niehs.nih.gov/docs/1999/suppl-3/409-419eskenazi/abstract. html



### Recent 

### studies have 

### demonstrated that 

### home environments 

### throughout the United States are 

### commonlycontaminated with 

### pesticides, 

### including organophosphate (OP), 

### carbamate, 

### organochlorine, 

### pyrethroid, and herbicide 

### compounds (1-12). Young 

### children may 

### be 

### highly exposed to 

### these 

### pesticides because oftheir normal 

### tendency to 

### explore their environ
### ment 

### orally, combined with their proximity to 

### potentially contaminated 

### floors, surfaces, and air. 

### Physiologic characteristics of

### young 

### children, such as 

### high intake 

### of 

### food, water, and air 

### per unit 

### of 

### body weight, may 

### also increase 

### their exposures (13). Because 

### children are 

### developmentally immature, 

### they may 

### also be at 

### higher risk 

### for adverse 

### health effects 

### (13). This paper reviews information on 

### children's 

### exposure to OP 

### pesticides and 

### potential adverse health effects. We 

### also outline our 

### planned research in 

### Monterey 

### County, 

### California,
to 

### investigate exposures to 

### children 

### living in 

### an 

### agricultural area 

### and 

### possible effects

on 

### growth, neurobehavioral 

### development, and 

### respiratorydisease. 

### Nationally, approximately 750-800 

### million pounds of conventional 

### pesticides

are 

### used 

### annually in 

### agriculture, 

### excluding sulfur, oils and 

### repellants (14). Total con

### ventional 

### pesticide use, 

### including home, 

### structural, and other 

### applications, aver

### ages 

### about 1 

### billion 

### pounds in 

### the 

### United
States. 

### During the 

### mid-1990s, national 

### pesticide use 

### levels have been stable 

### (15), although trends vary 

### by region. In 

### California, which has the 

### largest 

### agricultural output 

### of all 50 states, approxi

### mately 200 

### million 

### pounds of

### pesticidal active 

### ingredient are 

### used

### annually in 

### agriculture 

### (16). Pesticide use 

### data for California 

### suggest a 

### trend of 

### increasing

use 

### between 1991 

### and 1995 for 

### production 

### agriculture, postharvest treatment, structural 

### fumigation, and 

### landscape maintenance 

### (16). These 

### changes may be 

### due, in 

### part, to 

### unique 

### meteorologic and economic 

### factors, including 

### heavy rains, shifts to 

### lower 

### toxicity 

### compounds that 

### require 

### higher 

### volumes, and 

### changes in 

### planted acreage 

### (16-18). Agricultural use 

### of neurotoxic 

### pesticides, 

### including the 

### OPs 

### chlorpyrifos and 

### diazinon, was 

### also higher in 1995 than in 1991, most likely 

### due to 

### increased use on 

### cotton, and to a 

### lesser extent on oranges, alfalfa, apples, and 

### broccoli 

### (16,17). Overall, pesticide 

### use in 

### California appears to 

### be stable or increas

### ing, with annual 

### fluctuations making it 

### difficult to 

### identify long-term trends. 

### Pesticide residue in 

### food may 

### also 

### contribute to 

### children's exposures. In 

### response to concern 

### about low-level exposure, the 

### Food 

### Quality Protection 

### Act of 1996 (P.L. 

### 104-170) (19) was 

### unanimously passed by 

### the U.S. Congress to address pesticide 

### food safety issues 

### raised by the seminal 1993 

### National Academy of Sciences report 

### Pesticides in the Diets of 

### Infants and Children (13). This 

### report drew the 

### public's attention to the 

### specific 

### vulnerability of 

### children to many 

### pesti

### cides. The 

### National 

### Academy of Sciences committee 

### found that current 

### tolerances for 

### pesticide levels in 

### food are not health 

### based and may not 

### adequately protect 

### children. Congress 

### specifically directed the U.S. 

### Environmental Protection 

### Agency (U.S. EPA) to 

### reevaluate food tolerances 

### and establish health-based standards that
account 

### for 

### children's unique 

### sensitivity to 

### environmental toxicants. The law 

### requires the U.S. EPA 

### to consider all 

### nonoccupa

### tional sources 

### of

### pesticide exposure, 

### espe

### cially exposure to 

### compounds with similar 

### mechanisms of toxicity. The National 

### Academy 

### of Sciences recommended in 

### 1993 that the U.S. EPA 

### modify its

This article is part of the monograph on Children's Environmental Health and Disease Prevention Research. Address correspondence to B. Eskenazi, School of Public Health, University of California, Berkeley, 140 Warren Hall, Berkeley, CA 94720-7360. Telephone: (510) 642-3496. Fax: (510) 642-5815. E-mail: eskenazi@uclink4.berkeley.edu The authors thank M. O'Rourke forpreliminary information on pesticide levels in Arizona children. We also thank G. Solomon for review of earlydrafts. Finally, we thank our collaborators in the Center who have contributed to parts of this review, including 1. Tager, J. Leckie, V. Zartarian, T. Boyce, and M. Lipsett. This research is jointly funded by the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences award R826709-01-0. Received 2 February 1999; accepted 7 April 1999.

Environmental Health Perspectives * Vol 107, Supplement 3 * June 1999 409ESKENAZI ETAL.



### decision-making process 

### for setting 

### pesticide tolerances to 

### reflect the unique 

### characteristics 

### of the diets of 

### infants 

### and children and account 

### also for all 

### nondietary 

### intake of

### pesticides (13). 

### Findings from 

### several 

### small, cross-sectional studies 

### (3-6,8,12) indicate 

### that 

### nondietary
exposures to young 

### children 

### from residential contamination may 

### be an 

### important 

### component 

### of total pesticide exposure. 

### Unfortunately, our 

### knowledge about the 

### actual levels 

### of

### pesticide exposures 

### ofchil

### dren from 

### food and environmental exposures 

### and 

### their 

### potential health 

### effects is 

### extremelylimited. 

## Children's Exposure to 

## Pesticides
National 

### population-based surveys 

### of 

### pesticide urinary

### metabolites in 

### adults 

### indicate 

### widespread exposure to 

### pesticides, including 

### organophosphates, carbamates, 

### wood preservatives, 

### and 

### fungicides (20,21).
For

### example, Hill et

### al. (20) 

### detectedchlor

### pyrifos, an OP 

### pesticide, in 

### 82% 

### of 993 

### adults tested 

### through the National 

### Health and Nutrition Examination 

### Survey, 

### and 

### found a 

### 5-fold increase in 

### the proportion 

### of 

### adults with 

### levels over 

### 5 

### pg/L 

### compared to 

### earlier surveys, 

### suggesting increasing 

### exposure in 

### the 

### general population. OPs are 

### eliminated 

### from the 

### body after 

### 3-6 

### days (22), so 

### the 

### widespread detection of these 

### compounds indicates continuingexposure. 

### Biologic information on 

### children's 

### pesticide exposure is 

### very 

### limited. Hill et 

### al. (23) 

### reported

### detections ofdichlorobenzene and 

### wood preservatives in 

### 96% and 100%, 

### respectively, of 197 

### Arkansas 

### children, whereas 

### phenoxyherbicide metabolites were 

### found in 

### 20% 

### ofall 

### samples. Preliminary results from the 

### federal Agricultural Health 

### Study indicate detectable 

### pesticide residues in 

### children's urine 

### (8). Loewenherz et 

### al. 

### (24), 

### working in 

### Washington state, 

### found that 

### 44% ofchildren 

### of

### pesticide 

### applicators and 27% 

### of

### nonfarm, rural 

### children had 

### detectable OP 

### residues. In 

### preliminary data fromArizona, 

### chlorpyrifos was 

### detected in 

### 100% ofabout 40 

### children >6 

### years 

### ofage 

### sampled in 

### a 

### population-based survey, and 

### approximately 25% 

### of 150 

### children <6


### years 

### ofage 

### sampled in 

### an 

### agricultural area. Detection 

### limits in 

### the second surveywere 

### higher (25). Comparison 

### ofthese studies to 

### each other

### and to

### data

### reportedbyHill et

### al. (20) is 

### difficult because ofdifferences in 

### detection 

### limits, 

### sample type 

### (spot 

### samples

vs 

### first morning 

### void), and ages 

### ofparticipants. 

### Overall, these studies 

### suggest the 

### potential for 

### widespread low-level 

### pesticide exposure in 

### children and 

### the need for 

### population-based studies to

### establishnorms. 

### Pesticides enter 

### children's bodies via 

### dermal absorption, ingestion, 

### and inhalation. Exposure in 

### the home depends on 

### the frequency, duration, and nature (i.e., 

### dermal contact, 

### hand-to-mouth behavior) 

### of the child's interaction 

### with contaminated media such as 

### house dust. Children may 

### have 

### higher exposure to 

### pesticides than other 

### residents living in 

### the same conta

### minated environment, in 

### part 

### because
young 

### children spend more 

### of their time 

### indoors at 

### home (26,27). 

### Thus, they are 

### likely to 

### spend more time in 

### proximity to
any

### pesticides present in 

### their immediate environment. 

### The importance 

### of

### specific exposure-related behaviors, such as 

### handto-mouth activity, 

### will 

### be age 

### dependent, suggesting 

### that consequent exposure 

### levels and 

### pathways will vary 

### with age, as 

### has been 

### observed for lead exposure 

### (28). For 

### example, 

### children younger 

### than 6 

### months ofage may receive 

### their greatest exposures 

### through breast milk or 

### inhalation, but 

### dermal absorption and ingestion may 

### be the major 

### pathway of exposure 

### when 

### children begin 

### crawling and 

### placing their hands on 

### dustysurfaces and increasing 

### their 

### hand-tomouth behavior. The level 

### ofexposure may continue to 

### increase, given 

### that the normal 

### tendency ofyoung 

### children to 

### explore their environment 

### orally increases 

### through 2


### years 

### of age. 

### The 

### actual dose to 

### the child will 

### depend on 

### environmental concentrations 

### and the 

### efficiency of

### pesticide 

### uptake for the 

### different types 

### of exposure routes, i.e., 

### dermal contact versus 

### ingestion. To 

### date, direct observation and 

### quantification of children's 

### exposure-related activity 

### patterns 

### and their interaction 

### with their 

### environment is 

### very 

### limited. Time-activity analysis thus could 

### provide information about 

### age-specific exposure

### pathways. 

### To assess 

### time-activity patterns, most 

### researchers have 

### preferred self-administered time 

### diaries and interviews 

### (29,30). How
### ever, 

### these diaries are 

### subject to inaccurate 

### recall and thus 

### have limited 

### validity (31-33). Moreover, 

### they fail to 

### document microactivities 

### such as 

### dermal and hand-tomouth contacts, 

### which are 

### important 

### pathways 

### of exposure in 

### young children. Observational 

### techniques are 

### more 

### detailed and accurate 

### than 

### conventional methods of questionnaires and diaries for 

### recording suchmicroscopic data 

### (34-37). Leckie 

### and Zartarian 

### and co-workers 

### (36-39) have 

### successfullydevelopedvideotapingmethod

### ologies and video translation 

### software to 

### quantify children's 

### activity patterns 

### for 

### dermal and 

### nondietary contacts, 

### and 

### have piloted these techniques on 2- to 

### 4-year-old children 

### ofMexicanAmerican 

### farmworkers in 

### California (36). More extensive 

### data col

### lection is 

### needed on 

### children 

### ofvarious ages to assess 

### the 

### changing pathways and routes 

### ofexposure as 

### childrendevelop. 

## Exposures 

## of Farmworkers andTheir 

## Families Nationally, an 

### estimated 5 

### million farmworkers 

### work on

### America's 

### farms, including 

### approximately 1 

### million California residents (40). A

### growing 

### body 

### ofliterature indicates that resident 

### farm families, hired farmworkers, 

### and

### theirchildrenare 

### among

### thosemost 

### highly exposed to 

### pesticides (5,6,8, 10, 

### 12,24,41-49). These studies suggest 

### that 

### farm children can 

### be 

### exposed by the same 

### pathways as 

### other 

### children, namely 

### through consumption 

### of 

### contaminated 

### food, by 

### household use 

### ofpesticides, as 

### a 

### result of drift from nearby 

### agricultural applications, 

### by contaminated breast milk 

### from their farmworker 

### mothers, by playing in 

### the 

### fields, and 

### through pesticides tracked into 

### theirhomes bytheirparents or 

### otherhousehold members 

### working in 

### fields (5,6,8,10, 

### 12,24,41-43,50,51). For 

### example, 

### preliminary 

### data from pilot studies 

### conducted for the 

### Agricultural Health 

### Study in 

### North 

### Carolinaand Iowa 

### indicate elevated levels of 

### recently 

### applied pesticides in 

### the 

### food, homes, and

### bodies offarmfamilies 

### and their children 

### (8,10,12,43,44). In a 

### study of 88 

### children in 

### the 

### Yakima

### Valley, Washington, Loewenherz et 

### al. 

### (24) 

### reported more 

### frequent detection 

### of OP 

### metabolites in 

### children 

### of

### pesticide applicators compared
to 

### nonapplicators, particularly those living less than 200 

### ft from orchards. 

### Trends of increasing exposure 

### with 

### decreasing age 

### also 

### suggested that child activity is an 

### important
exposure

### variable. Simcox 

### et 

### al. (5) 

### studied 59 

### families in 

### the Yakima 

### Valley, and 

### compared levels of four 

### organophosphate (OP) 

### pesticides in 

### the homes 

### of

### hired 

### farmworkers, families 

### residing on 

### farms, and 

### nonagricultural families. 

### Chlorpyrifos was 

### detected in 

### 95% of the homes. House 

### dust concentrations were 

### consistently

### higher for 

### agricultural families than 

### for 

### nonagricultural 

### families, and pesti

### cide 

### applicators tended to 

### have 

### higher house dust concentrations 

### compared to 

### nonapplicators. There was a 

### 3-fold difference in 

### median 

### chlorpyrifos house dust concentration 

### between farmworkers who 

### did not 

### directly handle 

### pesticides and reference 

### families of nonfarmworkers 

### living in 

### agricultural communities 

### (median

Environmental Health Perspectives * Vol 107, Supplement 3 * June 1999 410CHILDRENAND PESTICIDES



### =172 ng/g 

### for 

### farmworker vs 

### 53 

### ng/g 

### for 

### nonagricultural 

### families). Bradman et 

### al. (6) 

### conducted a 

### pilot study 

### ofpesticide exposures to 

### children of migrant 

### farmworkers and 

### nonfarmworkers living in 

### a 

### largely Latino 

### community in 

### California's Central 

### Valley. Floor 

### dust sam

### ples and child hand wipes were 

### collected from the 

### homes of 10 

### families, 5 

### ofwhich had at 

### least one 

### resident 

### farmworker. Higher levels of the 

### OPs 

### diazinon (maximum = 

### 160 

### ppm), 

### chlorpyrifos (maximum

= 

### 33 

### ppm), 

### andmalathion (maximum = 

### 1.6 ppm) were 

### found in 

### house dust in 

### farmworker

### homes (6). 

### Residues 

### ofdiazinon and 

### chlorpyrifos were 

### detected on 

### the 

### hands of
two 

### and three farmworker 

### toddlers, respec

### tively, who also 

### lived in 

### the 

### homes with 

### the highest dust concentrations. A

### preliminary risk assessment 

### suggested that 

### diazinon
exposures in 

### children could exceed the U.S. EPA 

### Office of Pesticide Program's 

### oral 

### reference dose of9E-5 

### mglkg/day. 

### Overall, the 

### findings from these 

### studies suggest 

### that 

### inadvertent 

### carry-homes of 

### occupational 

### pesticides are 

### occurring 

### and that contamination in 

### the homes of 

### farm 

### families are 

### likely to 

### be

### higher than in 

### other homes. 

### Further, a 

### significant source 

### of
exposure to 

### farmworker families may

### derive from their

### residential proximity to 

### fields. 

## Potential Health 

## Effects of Exposure to 

## OP Pesticides
Studies of the 

### effects ofpesticide exposure

on 

### children's health have 

### been limited to 

### those of

### birth 

### defects, childhood cancer, 

### and acute 

### poisonings 

### following ingestion. 

### Several case-control studies have associated parental exposure to 

### pesticides or 

### pesticide

use in 

### the home with 

### childhood brain tumors, 

### leukemias and 

### lymphomas, testic

### ular cancers, 

### and other cancers 

### (52-55). Other studies 

### have 

### reported that 

### parental
exposure to 

### pesticides or 

### application of 

### pesticides in 

### the home is 

### associated with certain 

### birth defects 

### including neural tube and 

### otherbirthdefects 

### (56,57).
To 

### date, 

### only one 

### small 

### ecologic study has 

### examined whether low-level chronic
exposure 

### of

### children to 

### pesticides can 

### lead
to 

### adverse health consequences 

### (58). This 

### study of

### Yaqui 

### children in 

### Mexico 

### found that children 

### 4-5 years of

### age 

### (n = 

### 33) liv

### ing in an 

### agricultural 

### valley with presum

### ably higher 

### pesticide exposure 

### had 

### deficits in 

### tests 

### of stamina, 

### coordination, recall, and 

### ability to 

### draw a 

### person, 

### compared to 

### children 

### (n = 

### 17) 

### living in 

### the 

### foothills where there was 

### mostly 

### ranching. This 

### study, 

### although suggestive 

### of an 

### effect of 

### pesticides, is 

### limited 

### by small 

### sample 

### size, utilization of a convenience 

### sample, the 

### lack of 

### individual exposure 

### data, and no statistical control of

### potential confounders. At 

### present, the 

### only prospective study investigating 

### pesticides and 

### adverse 

### health effects is 

### the National Cancer 

### Institute/ U.S. EPA 

### Agricultural Health 

### Study, which is a 

### large 

### cohort study 

### of cancer in 

### midwestern and eastern 

### farmers and their 

### families (49). In 

### spite 

### of 

### the paucity 

### of 

### information concerning 

### the 

### potential health 

### effects in 

### children of chronic lowlevel exposure to 

### organophosphates, there is 

### substantial evidence in 

### developing rodents and 

### limited evidence in 

### adult humans 

### who have been 

### chronically exposed to 

### OPs that 

### low-level chronic
exposure to 

### organophosphates may 

### affect 

### neurologic 

### functioning, neurodevelopment, 

### and growth. Because OP 

### exposure may cause 

### dysregulation of 

### the autonomic 

### control ofairways, it 

### is 

### biologically plausible that exposure may 

### be 

### related to 

### the

occurrence 

### ofasthma in 

### children. 

## Effects of Acute 

## Exposure to 

## OP and 

## Carbamate Pesticides in 

## Children
The primary 

### effects of OP 

### and carbamate
acute 

### exposure are on 

### the 

### parasympathetic, sympathetic, and central nervous 

### system. 

### These 

### pesticides interfere with 

### the metabolism ofacetylcholine (ACh) 

### by 

### inhibiting 

### the enzyme 

### that 

### hydrolyzes it, 

### acetylcholinesterase 

### (AChE) (59). 

### ACh accumu

### lates at 

### the neuronal junctions, 

### resulting in 

### the continued 

### stimulation and 

### then suppression 

### of neurotransmission to 

### organs. 

### ACh is 

### the 

### chemical transmitter 

### of somatic
motor 

### neurons to 

### skeletal 

### muscle, 

### postganglionic 

### parasympathetic nerve 

### fibers, pre

### ganglionic fibers 

### ofboth 

### sympathetic and 

### parasympathetic nerves, and some 

### fibers in 

### the central nervous 

### system. 

### The accumulation 

### ofACh at 

### the motor 

### nerves 

### results in 

### weakness, fatigue, muscle cramps, 

### fasciculations, 

### and muscular weakness ofrespiratory 

### muscles. Accumulation at 

### the autonomic 

### ganglia results in 

### increased heartbeat and blood pressure, 

### pallor, and 

### hypoglycemia. Accumulation ofACh at 

### muscarinic 

### receptors 

### results in 

### visual 

### disturbances, tightness in 

### the chest and 

### wheezing due to 

### bron

### choconstriction and 

### increased bronchial 

### secretions, 

### and increased

### salivation, lacrimation, 

### sweating, 

### peristalsis (resulting in


### nausea, vomiting, cramps, 

### diarrhea), and urination. 

### Central nervous 

### system effects from ACh accumulation 

### include anxiety, 

### headache, confusion, 

### convulsions, ataxia, 

### depression of 

### respiration and 

### circulation, slurred 

### speech, tremor, and 

### generalized weakness 

### (59,60). Carbamates, unlike 

### OPs, do not 

### irreversibly inhibit ACHE. 

### Thus, their 

### activity is 

### quickly reversed 

### after excre

### tion 

### of the 

### pesticide 

### (61). Pregnancy may pose a 

### time 

### of

### increased risk

### because

### plasma AChE activity is already reduced, at 

### least during the 

### first two 

### trimesters 

### (62,63). The most 

### frequent acute 

### symptoms of OP 

### poisoning in 

### children 

### include miosis, excessive 

### salivation, nausea 

### and 

### vomiting, 

### lethargy, muscle weakness, 

### tachycardia, hyporeflexia, and 

### hypertonia, and respiratory distress 

### (60,64). Duration 

### of symptoms 

### depends on 

### the 

### dose, with the highest doses 

### resulting in 

### death. In 

### one 

### study, pneumonitis 

### developed in 

### about one-third of 

### poisoned children (64). OP-induced 

### delayed onset 

### peripheral 

### neuropathy (OPIDN), 

### reported for adults, has not been 

### reported in 

### children.



## Long-Term Sequelae of 

## Acute 

## Exposure to 

## OP and 

## Carbamate Pesticides in

## Adults
Although no 

### studies 

### have examined the 

### long-term sequelae 

### ofacute 

### pesticide poi

### soning in 

### children, some 

### studies in 

### adults suggest that 

### there are 

### residual effects. 

### Neuropsychologic investigations 

### ofpoi

### soned 

### farmworkers, pest 

### control 

### workers, and 

### industrial workers 

### tested a 

### number of 

### months to 

### years 

### after acute 

### exposure to various OP 

### pesticides have revealed deficits in 

### overall 

### abstraction, verbal and visual attention, 

### visual memory, visuomotor 

### speed, sequencing, visuomotor 

### problem 

### solving, motor 

### steadiness, motor 

### dexterity, and fine motor 

### speed (65-68). These workers report 

### anxiety, 

### depression, irri

### tability, confusion, and 

### impaired concentration 

### and memory. On 

### neurologic exam, 

### lower 

### vibrotactile sensitivity 

### has been reported (68,69). 

### High acute or 

### subchronic exposures to 

### OPs may 

### also result in 

### delayed neurotoxicity or 

### OPIDN 

### (59,70,71). OPIDN 

### usuallymanifests 1 

### to 

### 6 

### weeks after exposure 

### and may 

### result in 

### moderate to severe 

### peripheral neuropathies 

### lasting

### months, years, or 

### indefinitely (59). 

## Effects of Chronic 

## Exposure to 

## OP and 

## Carbamate Pesticides in

## Adults Although there are no 

### studies in 

### children

on 

### the 

### neuropsychologic effects of 

### chronic 

### pesticide exposure, small 

### studies ofchronic low-level 

### exposures of 

### farmers or 

### pest

Environmental Health Perspectives * Vol 107, Supplement 3 * June 1999 411ESKENAZI ETAL.



### control workers who 

### had levels ofAChE 

### within normal 

### limits 

### found no 

### differences in tests 

### of their neurobehavioral functioning 

### compared to 

### those of unexposed 

### controls (72) or in 

### a 

### pre/post exposure 

### comparison 

### (73). 

### Results ofother 

### studies in 

### adults 

### indicate that there may 

### be 

### mild 

### peripheral effects of chronic lower level
exposure as 

### indicated by slower reaction 

### times 

### (74), impaired proprioception (pos

### tural sway) (75), 

### decreased conduction 

### velocities in 

### motor 

### (median 

### and peroneal) 

### and sensory 

### (median and 

### sural) nerves 

### (76), 

### wider two-point 

### discrimination (77),

as 

### well as some 

### neurobehavioral effects such

as 

### increased anxiety 

### (78), decreased visuo

### motor 

### speed (65,79,80), 

### and 

### short-term verbal memory 

### (79). 

### Daily exposure to 

### OPs 

### that are 

### insufficient to 

### cause 

### signs 

### and symptoms 

### ofacute 

### poisoning may

### also pro

### duce an 

### influenza-type illness characterized by

### weakness, anorexia, 

### andmalaise 

### (81). In 

### chronic lower level exposures, 

### depression of 

### cholinesterase activity may 

### be 

### cumulative, and there is no 

### predictable correlation 

### between 

### the severity 

### of symptoms 

### and the 

### degree ofcholinesterase inhibition. 

## Animal 

## Evidence 

## for 

## Neurodevelopmental Effects of 

## Exposure to 

## OP Pesticides

There is a 

### strong 

### and growing 

### body of 

### evidence 

### linking exposure to 

### OP 

### pesticides during gestation or 

### the 

### early postnatal period and 

### neurodevelopmental effects in 

### animals. 

### These 

### effects may 

### be due to 

### the 

### direct impact 

### of OPs on 

### the 

### cholinergic system 

### ofthe 

### fetus, although effects on 

### cellular intermediates 

### such as 

### adenylyl cyclase (82) and 

### altered DNA 

### synthesis in 

### the brain 

### through 

### noncholinergic mechanisms 

### (83-85) have been 

### hypothesized. Table 1 

### summarizes 

### animal 

### studies investigating 

### different 

### organophosphate pesticides, dosing 

### regimes, and exposure routes 

### and their impacts on 

### the

### developing nervous 

### system. 

## Chlorpyrfos
Neurobehavioral tests 

### given 

### postnatally found that animals 

### exposed in 

### utero 

### demonstrated 

### decreased balance 

### (86), 

### increased 

### righting reflex time, 

### and poorer 

### cliff avoidance 

### (87,88). When exposure 

### occurred in 

### the 

### earlypostnatal period, there

was a 

### lowered 

### threshold for 

### convulsions 

### (89) as 

### well as 

### increased gait 

### abnormalities and tremors 

### (90) and deficits in 

### delayed alternation on

### mazes 

### (91). Some 

### studies suggest 

### that

### earlygestation


### maybe a 

### critical 

### period for the neurodevel

### opmental effects ofcertain

### pesticides. Muto 

### et 

### al. 

### (86) studied the effects of

### exposure to 

### chlorpyrifos in 

### rats 

### occurring both 

### during gestation 

### (gestationdays 0-7 

### and 7-2

### 1) and the 

### postnatal period. 

### They reported that 

### earlyprenatal exposures were 

### more 

### likely to 

### result in

### poorer 

### performance on 

### the 

### rotorod test 

### than exposures 

### during later gestation, which was in 

### turn, more likely to 

### result in 

### deficits than those occurring

### postnatally.
A 

### number 

### of

### mechanisms have been 

### proposed to 

### explain the 

### observed neurobehavioral effects in 

### animals. 

### Chanda 

### and Pope 

### (88) found that repeated exposure of 

### rodents to 

### low levels 

### of

### chlorpyrifos during gestation was 

### related to 

### inhibited levels of 

### AChE and

### downregulatedmuscarinic 

### receptors in 

### the 

### fetal brain. 

### Transient brain 

### AChE 

### inhibition also 

### has been consistently reported in 

### neonates 

### postnatally exposed to 

### chlorpyrifos (90-94). Other effects of 

### chlorpyrifos that, in 

### part, could 

### explain the 

### neurobehavioral impairment 

### include decreased muscarinic receptor 

### binding 

### (90,94,95), altered brain RNA concentrations 

### (96), 

### and inhibition 

### ofbrain DNA 

### synthesis 

### (84,85,97). For 

### example, after treating rats 

### on 

### postnatal 

### days 1-4 

### with a 

### dosage that 

### produced minimal AChE inhi

### bition (1 

### mg/kg), Dam et 

### al. 

### (85) reported 

### large deficits in DNA 

### synthesis in 

### the brain
stem

### and

### forebrain, withlessereffects on 

### the 

### cerebellum. Similar

### deficits in DNA

### synthesis were 

### observed after a 

### single 

### earlypostna

### tal exposure 

### but at a 

### slightly 

### higher dose 

### (97). 

### Earlypostnatal exposure to 

### chlorpyrifos 

### (postnatal 

### days 1-4 or 

### 11-45) also 

### altered RNA 

### concentrations in 

### the brain
stem

### and 

### forebrain ofrats 

### (96). Bytargeting RNA, 

### the macromolecule 

### that controls postmitotic processes 

### ofcell 

### differentiation and 

### growth, the chemical may 

### evoke alterations in 

### cell 

### function and number in 

### developingorganisms 

### (96). The 

### results ofthese studies indicate that OP

### pesticides couldcontribute to

### behavioral abnormalities in 

### young 

### animals 

### byproducing 

### cellular deficits in 

### the 

### developing brain. 

### Recently, Campbell et 

### al. (84) concluded that regions 

### rich in 

### cholinergic projections, such as 

### the brain stem 

### and forebrainmay

### be

more 

### affected than 

### the less 

### cholinergic regions such as 

### the cerebellum. However, 

### the maturational 

### timetable ofeach region 

### (brain stem 

### then forebrain then 

### cerebellum)
maybe an 

### important 

### factor in 

### determining relative 

### vulnerability. Nevertheless, there is 

### reasonable evidence that even

### subtoxic exposure to 

### chlorpyrifos during the critical 

### period ofbrain 

### development could

### produce 

### cellular, synaptic, 

### and neurobehavioral aberrations in

### animals 

### (97). 

## OdterOP 

### Pesticides

OPs other than 

### chlorpyrifos have 

### been associated with 

### loweredAChE in 

### the 

### brain of 

### rodents 

### exposed prenatally 

### [bromophos (98), dichlorvos 

### (99), dimethoate 

### (100), 

### methyl parathion (101), 

### quinalphos (102)]. Studies in 

### which animals were 

### exposed early in 

### the 

### postnatal period to 

### these other 

### organophosphate 

### pesticides have 

### also 

### reported inhibition of brain AChE 

### [dichlorvos (103), 

### diisopropylfluorophosphate (104), quinalphos 

### (105), 

### parathion 

### (92,93,95,106)] and 

### downregulation ofmuscarinic 

### receptors 

### [diisopropylfluorophosphate (104,107), 

### parathion (95,106)]. In 

### addition, evidence from a 

### single in vitro 

### study suggests that 

### prenatal
exposure to 

### organophosphates could alter human fetal brainAChE 

### levels. For exam

### ple, Banerjee et 

### al. 

### (108) reported a 

### dosedependent inhibition of 

### cerebellar AChE 

### activity in 

### human fetal brain cells 

### (8-10 weeks 

### gestation) treated with 

### 5 x 

### 10-11

- 

### 5 x 10-8 M 

### diisopropylfluorophosphate. Further research in 

### rodents has found reductions in 

### brain 

### weight, most 

### pronounced in 

### the 

### cerebellum and 

### brainstem, following OP 

### exposure during gestation 

### [dichlorvos (109), trichlorfon 

### (109-111)]. Neurobehavioral deficits such as 

### impaired maze 

### performance 

### [dichlorvos (99), diazinon 

### (112)], decreased 

### open-field activity 

### [sumithion (113)], impaired locomotion or 

### swimming 

### [trichlofon 

### (110), diazinon 

### (112)], and 

### reduced time on 

### the 

### rotorod test 

### [diazinon (112), sumithion 

### (113)] have also been 

### associated with prenatal 

### organophosphate exposure. In 

### addition, permanent alterations in 

### spontaneous motor 

### behavior (i.e., locomotion, rearing, and 

### total 

### activity) have been 

### observed in 

### mice exposed to a 

### single 

### subsymptomal dose of

### diisopropylfluorophosphate earlyin 

### the

### postnatal period (107).



## Other 

## Potential 

## Developmental Effects of OP 

## Pesticides

DesedBirth

### Weightand Altered

### Growth

A 

### number of the animal 

### studies reported above have 

### demonstrated a 

### decrease in 

### birth 

### weight or 

### bodyweight in 

### developing animals 

### exposed to 

### OPs. 

### Anticholinesterase agents such as 

### OPs mayhave a 

### nonspecific 

### regulatory effect on 

### growth, 

### perhaps by an influence on 

### placental transport 

### ofnutri

### ents 

### (112,114) or 

### by 

### altering the activity and reactivity 

### of the 

### adenylyl cyclase

Environmental Health Perspectives * Vol 107, Supplement 3 * June 1999 412CHILDRENAND PESTICIDES

Table 1. Reviewofthe literature of the effects of organophosphate pesticides on neurobehavioral functioning indevelopinganimals.a

Agent (dosemg/kg) Species Route Exposure period Neurodevelopmental effects

Mouse Diazinon Throughout gestation Lowerbirthweight



### (0.18, 9) Oral

Rat Methyl parathion

(1.0) Gavage Rabbit Dichlorvos

(9.0) Gavage

Rat Methyl parathion

(1.0, 1.5) Oral

Guinea pig Trichlorfon

(100) Gavage Pig Trichlorfon

(60) Oral

Rat Parathion

(1.3, 1.9) Subcutaneous

Rat Sumithion

(5, 10, 15) Gavage

Rat METASYSTOX-R

(Methyl demeton) (0.5, 1.5, 4.5) Oral

Rat Parathion

(0.882) Subcutaneous

Rat Methyl parathion

(7.8) (adult: 18) Parathion (2.1) (adult: 18) Chlorpyrifos (45) (adult: 279) Subcutaneous

Rat Chlorpyrifos

(0.03, 0.1, 0.3) (0.1, 0.3) Intraperitoneal

Rat Methyl parathion

(<7.8) (adult: < 

### 18)b Parathion

(<2.1) (adult: < 

### 18)b Chlorpyrifos

(<45) (adult: < 279)b Subcutaneous GD 7-15

PND 6-16 or 16

GD 6-12

GD 36-38 or 51-53

GD 55 or 55 and 70

PND 5-20

GD 7-15

GD 6-15

PND 5-20

PND 7 andadult

GD 0-7 or 7-21
PND 3, 10 or 12, 6-10

PND 7 and adult Decreased rate of

### postnatal weight

### gain

Balance 

### (rotorod), swimming, and maze 

### (speed) effects Nodifferences in

### auditorystartle, visual cliff response, or 

### open-field motor

### activity Slightchanges in 

### learningability as measured

### bysimple two-choice maze Effects on

### open-fieldactivity

InhibitedAChEactivity inall brainregions tested; recovery slower inanimals 

### exposed over 10

### days thanafter a

### singledose Decreased serotonin concentration inbrainstem 

### (22%), mesencephalon 

### (26%), and

### hippocampus 

### (59%) afterprolonged exposure Altered

### postnatal development ofbrain

### cholinergic neurons ReducedAChE

### activityinall brain

### regions 

### (1.5

### mg/kg) Increased cholineacetyltransferseactivities inall brainregions (1.5

### mg/kg) Subtlealterations inselected behaviors: 

### impaired cage emergence, accommodated locomotoractivity, and operantbehaviorin amixed

### paradigm No

### morphologicchanges in

### hippocampal orcerebellartissue Disturbances of locomotion Reducedbrain

### weight, particularlycerebellum, hippocampus, 

### thalamus, andcolliculi
Dose-related cerebellar

### hypoplasia Ataxia not observed in neonates

Dose-dependent reductions inAChE activityandmuscarinic receptor

### binding inthe cortex Nodifferences in mostreflexmeasures, eye opening, or incisor

### eruption during thepreweanling

### period Small deficits in tests of

### spatial memoryinboththeT-maze andthe radial

arm maze

### duringthepostweanling

### period
Dose-relateddecrease in open-fieldactivityand motorcoordination 

### (rotorod) Alterations inacquisition and extinction of a conditioned escape response Increased social interactions No significantbehavioral effects at lowestdose (5mg/kg)

Nodifferences infetal brainAChE Nodifferences inneonatal survival, growth, anddevelopment No alteration of sensory orreflexfunctions, maze learningability, or openfield

### activity
Cellular

### disruptionandnecrosis inthedentate gyrus and CA4 regions ofthe hippocampus 

### Depressedhippocampal AChE (73%) andmuscarinic 

### [3H1 QNBbinding 

### (36%)
at PND 12
ChE inhibition inwholebrain, plasma, anderythrocytes (transient) Maximal brainChE inhibition (>78%) similar inboth age groups ChEactivityrecoveredfaster in neonate

Lowerbodyweight Balance effects (rotorod) Effects onopen-field motorbehavior Effects earlygestation > lategestation > postnatal Inhibition ofbrainandplasma ChE activity in both neonate andadult Good correlation betweenbrain ChE (r= 0.93) orplasma ChE (r= 0.99) inhibitorypotencyand acutetoxicity



### (Continued)

Environmental Health Perspectives * Vol 107, Supplement 3 * June 1999 Author, year SpykerandAvery, 1977 

### (112)

Crowder etal., 1980 (132)

Maslinska etal., 1981 (103)

Gupta etal., 1985(101)

Berge etal., 

### 1986(110)

Pope etal., 1986 (133)



### Stamper etal., 1988 (95)

Lehotzkyetal., 1989 

### (113)

Clemens etal., 1990 (134)

Veronesi and Pope, 

### 1990(106)

Pope etal., 1991 

### (92)

Muto etal., 

### 1992(86)

Pope and 

### Chakraborti, 1992(93)

413ESKENAZI ETAL.

Table 1. Continued.

Agent (dosemg/kg) Author/Year Species Route Exposure period Neurodevelopmental effects

Srivastava etal., Rat Quinalphos GD 6-20



### (0.5, 1.5) Gavage

Rat Diisopropylfluorophosphate 

### (0.5-1.0) Subcutaneous

Rat Chlorpyrifos



### (0.3-10) Subcutaneous

Rat Chlorpyrifos



### (40) Subcutaneous

MehI etal., Guineapig Dichlorvos 1994 

### (109) 

### (15-30) Trichlorfon (125) Subcutaneous
Santhoshkumar Rat 

### Bromophos and 

### Shivanandappa, 

### (500) 1994 

### (98) Gavage PND 4-9 or4-20

PND 16 or 17

PND 7-10

GD 42-46

GD 18 ReducedAChE activity infetal brain (0.5-1.5mg/kg) andplacenta (1.5mg/kg)

Nodifferences infetal weight oranomalies

Inhibition ofAChE Downregulation ofmuscarinic receptorrecognitionsites These alterations maydelaythematuration of thecholinergic systemand
mayaccountfor some long-lasting neurotropic effects observedafter developmental exposure
More rapid amygdala kindling intreated animals Proconvulsant effectwas dose related Increased excitability oftheamygdala
AChE activity

### 55-60% controls Less inhibition ofAChE in neonate relative toadult Muscarinic 

### [3H] QNB receptorbinding in cortex, hippocampus, and striatummarginallyaffected (5-11% 

### reduction) inneonate Basal motoractivity levels notaffected
Reduction inbrainweight Mostpronounced in cerebellum, medulla, thalamus, hypothalamus, and quadrigeminal plate

AChE inhibition infetal brain startedat 2 hrand reached a maximum
at 16 hrpostexposure 

### (transient) Recoveryalmost completebyPND 1 

### SensitivityofChE inhibition invivo: maternal serum >maternal brain > fetal brain

Rat Chlorpyrifos

(90, 120, 240) Subcutaneous

Mouse Diisopropylfluorophosphate (1.5) Gavage

Rat Chlorpyrifos

(200) Subcutaneous

Rat Dimethoate

(7, 10.5, 14, 28) Dichlorovos (1, 1.5, 2, 3.9) Methyl parathion (0.2, 0.3, 0.4, 0.9) Gavage

Rat Dichlorvos

(0.97-3.88) Oral Rat Chlorpyrifos

(2.0) Subcutaneous

Rat Chlorpyrifos

(0.1, 3, 15) gavage (0.1, 1, 5) oral PND 21

PND 3, 10, or 19

GD 12

Threegenerations Males and nonpregnant females: 5days/week Pregnant females throughout gestation and lactation Throughout gestation and lactation

PND 1

GD 6-15

Two generations: 5days/week Signs of severe poisoningprevented behavioral testing athighest dose

Transient memory impairment on maze (120 mg/kg) Dose-related inhibition of brainAChE buttransient Reducedmuscarinic binding of 

### [3H]QNB in frontal cortex (240 mg/kg)
Altered spontaneous motorbehavior (increased locomotion, rearing, and total activity) observed at adult age of 4 months Decreased muscarinic receptordensityatadult age Persistent effects found inadultmice exposed to single subsymptomal dose

on PND 3 or 10; not in animals exposed on PND 19
Decreased brainAChE activity inbothdams (85-88%) and fetuses (42-44%) By PND 3, brainAChE still inhibited in pups (30%); less thanfor dams (82%)
Invitroinhibition of maternal and fetal brainAChE activity indicatedthat prenatal AChE activity was somewhat more sensitive Righting reflextime was increased in PND 1 pups No differences in righting reflex at PND 3

Altered electrophysiological function inprimary somatosensory, visual, andauditory cortex Increased mean frequencyand EEG index, anddecreased meanamplitude dose dependent Changes more expressed in second and thirdgenerations AChE inhibition in brain (significant athighest dosages)

Increased maze running time and errors AChE in brain 40-65% control Changes were dose related Inhibition of DNAsynthesis within 4 hrof treatment and at 8 days of age in all brain regions Concludedthat lowdosestargetthedevelopingbrainduringcriticalperiod inwhich cell division isoccurring, effects that mayproduceeventual cellular, synaptic, andbehavioral aberrations afterrepeated orprolonged subtoxic exposures
No teratogenic effects found inanimals exposed ongestational days 6-15

Two generation study: AChE inhibition in brain (52% control) anddecreased bodyweight in Fl litters (5mg/kg)

(Continued)

Environmental Health Perspectives
* Vol 107, Supplement 3 * June 1999 1992 (102)

Balduini etal., 1993 

### (104)

Wurpel etal., 1993 

### (89)

Chakraborti
etal., 1993 

### (94)

Stantonetal., 1994 

### (91)

Ahlbometal., 1995 

### (107)

Chanda etal., 1995 

### (87)

Nagymajtenyi
etal., 1995 

### (135)

Schulz etal., 1995 

### (99)

Whitneyetal., 1995 (97)

Breslin etal., 1996 

### (115)

414CHILDRENAND PESTICIDES

Table 1. Continued.

Agent (dosemg/kg) Author/Year Species Route Exposure period Neurodevelopmental effects

Chanda and Rat Pope, 1996(88)

Srivastava and Rats Raizada, 1996 (100)



### Campbell etal., Rat 1997(84)



### Song etal., Rat 

### 1997(82)

Dametal., Rat 1998(85)



### Gupta etal., Rat 

### 1998(105)

Hjelde etal., Guin 1998(111)

Johnson et

### al., Rat 

### 1998(96)

Moserand

### Pedilla, Rat 

### 1998(90) Chlorpyrifos GD 12-19 (6.25-25) Subcutaneous

Dimethoate (3.75, 7.5, 15, 

### 30) Gavage

Chlorpyrifos 

### (1,5) Subcutaneous Chlorpyrifos 

### (1,5) Subcutaneous

Chlorpyrifos (1.0) Subcutaneous

Quinalphos 

### (0.5) Oral

neapig Trichlorfon 

### (25-200) Gavage or subcutaneous



### Chlorpyrifos 

### (1,5) Subcutaneous



### Chlorpyrifos (15, 80) 

### Gavage GD 6-20

PND 1-4or 11-14

PND 1-4or 10-14

PND 1-4

PND 10-21 or 10-45

GD 42-44 or 34-53

PND 1-4or 11-14

PND 17 andadult AChE inhibition

Righting reflexandcliffavoidance affected Dose-related downregulation ofmuscarinic receptors Low-level, repeatedexposures causedextensive neurochemical and neurobehavioral changes

Dams exposed to 15 and 30 mg/kg produced 20 and 60% mortality, respectively; highestdosage group notconsidered fortoxicityevaluation Inhibition ofAChE activity infetal brainandplacentadosedependent; less than fordams Reducedfetalweight
No teratogenic effects Significantmortalityand severecell loss inbrainstemathigherdose 

### (PND 1-4) Cell loss inforebrain (PND 11-14); loss occurredaftertreatment DNA levels elevated incerebellum afterexposure, then subnormal Deficits inadenylyl cyclasecascade inforebrain, cerebellum, andheart Disrupted signaling function intransduction ofbothcholinergic and adrenergic signals Concludedthatdisruptionofcell development is not restrictedto cholinergic targets, noreventothecentral nervous system Decreased DNAsynthesis inbrainstem and forebrain on PND 5 

### (24hrafter lasttreatment) No effects seen 4 hraftertreatment Smallerdeficits incerebellum Nodifferences inRNAorproteinsynthesis
DecreasedAChE inthebrainandbloodbuttransient Increased superoxide radical generation inbrain: 43% byPND 21 and 59% 

### byPND 45 Enhancedbrain lipidperoxidation: 28% byPND 45 Producedcerebral oxidative stress, whichmayaffectcentral nervous systemfunction
Reducedweight inalmostall regions ofthebrain, especially cerebellum, medulla, andhypothalamus Minimumdoserequired foreffectwas 100mg/kg over3 consecutivedays 

### Suggestedalkylation of DNAoreffects on its repaircapabilityaspossible mechanisms
AlteredRNAconcentrations inthebrain stemandforebrainatsubtoxicdoses Targetedmacromolecules thatcontrol cell differentiation duringcritical 

### postmitotic

### period; mayelicitdelayeddevelopmental 

### neurotoxicityas aresult Concludedthatthedevelopingbrain is a selectivetargetforchlorpyrifos
Behavioral effects 

### (loweredactivity, gaitabnormalities, tremors, 

### smacking) andChE inhibition at 5-fold lowerdosethanadult Maximal effects occurred at 6.5hrafterdosing Bloodandbrain ChE recoverybyPND 24 Decreased muscarinic receptor 

### (QNB) binding

Abbreviations: AChE, acetylcholinesterase; ChE, cholinesterase; GD, gestational day; PND, postnatal day; QNB, quinuclidinyl benzilate. 'All reviewed studies contain an unexposed control group for comparison. hAnimalswere treatedwithgradeddoses uptothemaximumtolerateddose (MTD).



### signaling cascade, whichwould

### disrupt cell 

### development in 

### all areas 

### of the 

### body, not 

### onlythose 

### cholinergicallyregulated (82).
Muto et 

### al. 

### (86) 

### reported lower 

### body weight in rats

### exposedduring the 

### first 7 

### days of

### gestation to 

### chlorpyrifos (0.03 

### mg/kg); with 

### higher doses 

### they found a 

### decrease in 

### the 

### length ofthe limbs 

### (0.1 and 0.3 

### mg/kg) and head 

### circumference 

### (0.3 

## mg/kg). Other studies have 

### reported a 

### decrease in 

### pup 

### weight (115) and a 

### decrease in

### weight gain 

### postnatally 

### following exposure to 

### chlorpyrifos 

### (88) or 

### diazinon 

### (112) 

### during gestation. 

### Spyker andAvery 

### (112) also 

### reported lower birth

### weight and a 

### slower rate 

### of

### postnatal 

### weight gain in 

### mice 

### exposed to 

### diazinon (9 

### mg/kg) throughout gestation. In 

### rats, low levels 

### oftwo 

### carbamates anda triazine

### herbicide administered 

### postnatally interacted to 

### increase 

### thyroxine levels 

### and alter levels 

### of somatotropin, hormones that 

### regulate growth (116). 

## Potential Respiratory

### Health

## Effects

Much

### ofthe animal literature reviewed

### here has 

### focused on 

### the central nervous 

### system 

### effects of 

### organophosphate exposure. Because OP 

### pesticides exert 

### their 

### phar

### macologic effects 

### through inhibition of 

### AChE, both

### short- and 

### long-termeffects on autonomic 

### regulation are 

### prominent 

### features in 

### the 

### toxicology of this class 

### ofpes

### ticides 

### (76,117). No 

### previous 

### work has addressed the autonomic 

### sequelae ofpes

### ticide exposure per

### se, yet

### disorders ofautonomic 

### regulation may

### be one 

### ofthe earliest and most sensitive measures 

### of 

### long-term physiologic effects of exposures in 

### infants 

### andyoung

### children.

Environmental Health Perspectives * Vol 107, Supplement 3 * June 1999

3

415ESKENAZI ETAL.



### Similarly, the parasympathetic nervous 

### system

### provides theprincipal neural control 

### oflung airway tone. There are considerable 

### data indicating that dysregulation ofboth 

### parasympathetic (cholinergic) and sympathetic autonomic control ofairways, suchas 

### bypesticide exposure, maybe important in the 

### occurrence 

### ofasthma and its severity (118). Dysregulation ofparasympathetic 

### function, as 

### measured by respiratory sinus 

### arrhythmia, predicts the onset 

### ofwheezing in adults (119). Although there are 

### few direct studies of the effects of OP 

### and car

### bamate 

### pesticide exposure on 

### asthma 

### risk, farmworkers' exposure to 

### carbamate pesti

### cides has been associated with 

### the occur
### rence ofasthma after adjustment 

### for other relevant 

### factors (120). 

### Professional fumigators 

### reportedly 

### have an 

### increased occurrence 

### of

### allergy and asthma in 

### parallel with

a 

### higher risk 

### of a > 

### 20% 

### decrease in 

### red 

### blood cellAchE (121). Exposure to 

### chlor

### pyrifos has also been associated with an 

### increase in 

### the occurrence 

### ofatopic 

### conditions 

### (122). 

### Although none 

### ofthese 

### studies involved children, they raise the 

### prospect 

### that pesticide exposure 

### could be important 

### etiologic and 

### morbidity-modifying factors in theoccurrence 

### of

### childhoodasthma. 

## Biologic 

## Plausibilityforthe Effects of 

## Low-Level 

## Chronic Pesticide 

## Exposure in

## Children

Tests on 

### young 

### rodents demonstrate a 

### progressive 

### decrease in 

### susceptibility to OP 

### pesticideswith increasingage 

### (13,123-125).
In 

### some 

### cases, the 

### lethal dose in 

### immature 

### animals is 

### only 1% 

### ofthe adult lethal dose (92,93,97). A 

### study ofrats 

### found that ani

### mals 1 

### and 7 

### days ofage 

### tolerated only 4% and 17% of the 

### adult dose, 

### respectively (92,93,97). 

### Seven-day-old rats were 

### 2.3, 8.6, and 6.2 times more sensitive 

### than 

### adults to 

### the acute 

### toxicity 

### of

### methyl para

### thion, parathion, and 

### chlorpyrifos, respec

### tively (92). In 

### humans, children have had 

### higher fatality rates 

### than adults in 

### several

cases 

### ofOP

### poisoning 

### (13). Young animals 

### maybe more 

### susceptible to 

### the toxic 

### effects of 

### organophosphates due to 

### lower

### activityof

### detoxifying enzymes such as 

### paraoxonase that deactivate active OP 

### metabolites 

### (e.g., paraoxon, chlorpyri

### fos-oxon) (123,126-131). For example, Mortensen et al. 

### (126) reported markedly lower

### plasma and liver chlorpyrifos-oxonase levels in 

### neonate 

### compared to adult 

### rat tissue. 

### They concluded that the 

### higher sensi

### tivity of

### young rats to acute 

### chlorpyrifos toxicitymay not be 

### explained by increased 

### sensitivity 

### of the 

### target enzyme, brain AChE, but it may be partially explained 

### by a 

### deficiency of 

### chlorpyrifos-oxonase activity (126). 

### Although young animals are more sensitive 

### than adults to 

### the acute toxic 

### effects of 

### chlorpyrifos, some 

### researchers have 

### suggested that 

### lower level chlorpyrifos
exposures may 

### produce more extensive 

### neurobehavioral 

### effects in the adult rat 

### than in 

### the neonate 

### (94). In 

### addition,

more extensive 

### changes have been found in 

### cholinergic parameters in 

### the maternal 

### brain compared to 

### the 

### fetus or neonate 

### (88). 

### Developing animals also appear to



### recover more 

### quickly from cholinesterase inhibition than the 

### adult (92,98), 

### andmay be 

### less susceptible to 

### developing OPIDN 

### (71). However, 

### repeated low-dose chlorpyrifos exposure 

### during gestation 

### has been 

### associated with persistent 

### neurochemical and neurobehavioral changes in 

### developing rodents (88).
In 

### summary, 

### young 

### children may 

### be 

### especially vulnerable to 

### pesticides because 

### ofthe sensitivity 

### of their 

### developing organ systems combined with a 

### limited 

### ability to 

### enzymatically 

### detoxify these chemicals (13,123,126-131). 

### According to 

### the National 

### Academy of Sciences 

### (13), 

### children's OP 

### exposures are 

### of

### special concern 

### because "exposure to neurotoxic com

### pounds at 

### levels 

### believed to 

### be safe 

### for adults could result in 

### permanent 

### loss of 

### brain 

### function if it 

### occurred during the 

### prenatal and 

### early childhood period of brain 

### development" (13). Because 

### there is

so 

### little 

### information available on 

### the levels 

### and routes 

### ofchildren's 

### pesticide exposure, it 

### is not 

### feasible to 

### conduct a 

### risk assessment 

### predicting the 

### likelihood of adverse effects based on 

### animal 

### studies. Thus 

### far, there are no 

### data in 

### children to 

### support or 

### refute the 

### hypothesized health 

### effects of 

### chronic low-level 

### pesticide exposure. 

## Future Directions

There is 

### clearly a 

### lack 

### of information on 

### the sources, 

### pathways, and levels ofpesti

### cide exposures 

### of

### children, and in 

### particu

### lar, ofthose 

### children at

### highest risk

### because 

### they live in 

### agricultural communities. 

### Similarly, there is a 

### dearth of information

on 

### whether low-level 

### chronic exposure to 

### pesticides is 

### associated with 

### adverse 

### health effects. The 

### goal of the Center 

### for Children's Environmental Health Research
at 

### the University of

### California, Berkeley is
to 

### address these questions 

### by conducting a 

### longitudinal cohort 

### studyof

### approximately 500 pregnant women 

### and 

### their children who live in a 

### rural 

### agricultural community 

### in the Salinas 

### Valley of

### Monterey County, 

### California. 

### The 

### specific aims of

### this Center for the 

### HealthAssessment of

### Mothers and 

### Children of 

### Salinas, or 

### CHAMACOS (which means 

### "little child" in 

### Chicano 

### Spanish), are to 

### a) 

### characterize OP 

### exposure 

### levels and 

### pathways in 

### pregnant

women and their 

### children; b) 

### determine the

### predictors ofOP levels in the 

### bodyand 

### home; c) 

### describe the exposure-prone behavior of 

### children at 

### different develop

### mental stages 

### using time-activity analysis; and 

### d) follow up the children to 

### 3 years of


### age to 

### determinewhether exposure in utero 

### and/or during the 

### postnatal 

### period is 

### associated with 

### poor 

### neurodevelopment (assessed by tests 

### of the central 

### and auto

### nomic nervous 

### system), slower and stunted growth, and 

### increased prevalence 

### ofrespi

### ratory symptoms 

### and disease. Our 

### ultimate goal is to 

### involve community partners in 

### planning, coordinating, and 

### conducting an 

### intervention to 

### reducepesticide exposures to 

### young children in 

### this 

### agricultural community 

### and to 

### evaluate the 

### efficacyand 

### sustainability of the intervention. To 

### accomplish our 

### goals, we 

### have established a 

### multidisciplinary partnership comprised of 

### farmworkers, health care 

### providers, growers, 

### journalists, scientists, 

### educators, and 

### representatives 

### of 

### community groups 

### and state 

### and countyhealth 

### and 

### agricultural 

### departments. 

### We 

### are 

### hopeful that the results of this 

### studywill 

### benefit this community 

### and 

### agricultural communities, in 

### general, and will 

### directly contribute to 

### the 

### information
necessary 

### for the 

### implementation of the Food

### QualityProtectionAct.

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