CHILDREN’S EXPOSURE TO PESTICIDES: PRIORITY OF CAUSE AND SUSCEPTIBILITY Chensheng (Alex) Lu, PhD, MSMark and Catherine Winkler Assistant Professor of Environmental Exposure BiologyDepartment of Environmental HealthHarvard School of Public Health

MORBIDITIES OF CHILDHOOD IN US

Kogan MD, et al. Pediatrics 2009; Branum AM, et al. Paediatr Perinat Epidemiol 2002;16:8-15; Hedley AA, et al. JAMA 2004;291:2847-50. Lanphear BP, et al.Pediatrics 2001 e98. Froehlich T, et al. Arch Ped Adolesc Med 2007;161:857-864; Braun J, et al. Environ Health Perspect 2008;116:956-962.

INCIDENCE OF ABDOMINAL WALL DEFECT (AWD) IN INDIANA, THE MIDWEST, AND NATION-WIDE 1,2

1. Data obtained from the CDC natality set comparing the birth rate of AWD in Indiana (dotted line), in theMidwest (dashed line), and nationally (solid line).2. Mattix, Winchester, Scherer (2007). Incidence of absominal wall defects in related to surface water atrazine and nitrate levels. J. Pediatric Surgery. 42:947-949.

AWD RATES OF INDIANA COMPARED WITH SURFACE WATER NITRATE AND ATRAZINE LEVELS

FROM 1990-2001

Data obtained from Indiana birth certificate registry.Mean nitrate levels (ppm) shown by the dotted line.Mean atrazine levels (ppm) shown by the solid line.AWD incidence by month of last menstrual period shown by the dotted line with square data points.

THE UNITED STATES BIRTH DEFECT RATES1 BY MONTH OF LAST MENSTRUAL PERIOD (LMP) VERSUS

ATRAZINE CONCENTRATIONS IN SURFACE WATER2

1. Winchester, Huskins, & Ying (2009) Agrichemicals in surface water and birth defects in the US. Acta Pediatrica, 98:664-669.2. United States Geological Survey’s National Water Quality Assessment data

CONCLUSIONS• Elevated concentrations of agrichemicals,

such as atrazine and nitrate, in surface water from April to July coincided with higher risk of birth defects in live births with LMPs in April–July,

• While a causal link between agrichemicals in water bodies and birth defects cannot be proven from these studies, an association might provide clues to common factors shared by both variables.

MORBIDITIES OF CHILDHOOD IN US

Kogan MD, et al. Pediatrics 2009; Branum AM, et al. Paediatr Perinat Epidemiol 2002;16:8-15; Hedley AA, et al. JAMA 2004;291:2847-50. Lanphear BP, et al.Pediatrics 2001 e98. Froehlich T, et al. Arch Ped Adolesc Med 2007;161:857-864; Braun J, et al. Environ Health Perspect 2008;116:956-962.

MORBIDITIES OF CHILDHOOD IN US

AUTISM’S DILEMMA• A single gene mutation [MET] doubled a

child's susceptibility to autism, a Vanderbilt study concluded (Levitt et al., October 2006),

• It is hypothesized that the common, functionally disruptive [MET gene variant] can, together with other vulnerability genes and environmental factors, precipitate the onset of autism," Levitt and colleagues suggested.

AUTISM’S DILEMMA• A 2009 paper* has shed some light in

linking autism to environmental factors;• Autism’s cumulative incidence in 4-year-old children living in California rose from 6.2 for 1990 births to 42.5 births for 2001 per 10,000 births,

• Changing age at diagnosis explained a 12% increase,

• Inclusion of milder autism cases explained a 56% increase.

* Hertz-Picciotto and Delwiche, Epidemiology, 20(1):84-90

Cumulative incidence of autism by birth cohort from 1990 to 2003, at ages 1–9 years, California Departmental of Developmental Services database. Hertz-Picciotto and Delwiche, Epidemiology, 20(1):84-90.

Annual incidence rates of autism based on the administrative database of the California Department of Developmental Services, 1990 through 2006, by quarter. Each point represents the number of new cases in each quarter divided by the population of children in the respective age group at the midpoint of the year (an estimate of the number of child-quarteryears), and then multiplied by 4 to obtain an annualized rate. The fitted lines represent smoothed Loess curves and the vertical line at year 2003 quarter 3 is the time at which access to state servicesbecame more restrictive. Hertz-Picciotto and Delwiche, Epidemiology, 20(1):84-90.

110 per 10,000 weighted ASD point prevalence in US children aged 3-17 in 2007 (Kogan et al. 2009).

AUTISM’S DILEMMA• What we have learned;

• Autism incidence shows no sign yet of plateauing,

• The progression of autism can not solely be attributed by genetic causes,

• Other (environmental) factors have yet to be quantified,

• Timing of chemical exposure presumably critical.

RECENT AUTISM FINDINGS• Researchers confirmed maternal age

associated with autism http://www.niehs.nih.gov/news/newsletter/2010/march/science-researchers.cfm

• Increased parental age may foster changes in fetal gene expression,

• Environmental exposure independent of the genetic makeup lead to histone modification and alter DNA methylation paterns.

NON-PERSISTENT PESTICIDE EXPOSURES(ORGANOPHOSPHATES, PYRETHROIDS)

• Widely available for human (both residential and agricultural) uses,

• Quickly distributed, metabolized, and excreted from human body (short biological half-lives from hours to a few days),

• Complex chemistry, human metabolism, and biochemical reactions/interactions,

• Human exposure, particularly children’s, not static but fluctuating from day to day, and from different sources/pathways,

• A challenge for exposure/epidemiological/health effect research.

2 22 12 32 32 32 32 32 22 32 32 32 32 12 32 32 0N =

S e q u e n t i a l d a y

1 61 51 41 31 21 11 0987654321

M

D

A

d

a

ily

c

o

n

c

e

n

t

r

a

t

io

n

(µ

g

/

L

)

2 0

1 5

1 0

5

0

- 5

Conventional Diets

Conventional Diets

Organic Diets

MALATHION EXPOSURE PROFILE AS MEASURED OF URINARY MDA CONCENTRATION (µg/L) IN

URBAN/SUBURBAN CHILDREN*

*Lu C. et al. (2006). Environ Health Perspect, 114(2): 260-263. PMID: 16451864.

ONE-YEAR MALATHION EXPOSURE PROFILE AS MEASURED OF URINARY MDA CONCENTRATION

(µg/L) IN URBAN/SUBURBAN CHILDREN*

* Lu C. et al. (2008). Environ. Health Perspect. 116(4)537:542. PMID: 18414640.

VULNERABILITY OF FETUS AND YOUNG CHILDREN FOR PESTICIDE’S NEUROTOXICITY

• Rapid brain development• Exposure to pyrethroids up-regulation dopamine

transporter (DAT) and therefore increasing the susceptibility of dopamine neurons to neurotoxic pesticides1,

• Insufficient detoxifying enzymatic (PON1) activity• OP-oxonases, enzymes responsible for hydrolyzing

OPs’ extreme potent intermediate metabolites, OP-oxon2,

• Polymorphism of PON1 activity reported to be associated with autism spectrum disorder3 and childhood brain tumor4 in children.

1. Elwan et al. (2006) Toxicol. Appl. Pharmacol. 211(3) pp. 188-97.2, Furlong et al. (2006), Pharmacogenet. Genomics 16, pp. 183–190. 3, D’Amellio et al. (2005), Mol. Psychiatry 10(11), pp. 1006-16.4, Nielsen et al. (2005), Environ Health Perspect 113(7) pp.909-13.

PESTICIDES IN YOUR PEACHES* – MONICA ENG, TRIBUNE REPORTER

• Chicago Tribune and USDA studies found pesticides, some in excess of US EPA rules, in the fragrant fruits, like peaches More than 60 chemicals were found in the

recent USDA survey for peaches, For the top 50 chemicals found in the

CONVENTIONAL peaches, They found 3 chemicals in peaches

purchased from local FARMERS’ MARKETS, They found 1 chemical in ORGANIC peaches

grown in California.

“As w

e munch into the peach

season, shoppers face an array of choices for the sam

e fuzzy fruit but little guidance on w

hich type to pick …

……

.” August 12, 2009

* http://www.chicagotribune.com/health/chi-0812-peaches-pesticides_mainaug12,0,2494206.story

GENETICS VS. ENVIRONMENT

“ Why did this particular child living in Chengdu China have autism? ”

“ Why does this particular population of children living in Chengdu China have so many autistic cases? ”

If causes can be removed, then susceptibility ceases to matter.

- Geoffrey Rose, MD (1926-1993) -