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Section II Outline
Links: Chemicals and Disabilities
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Basic Toxicology
Lead
Mercury
PCBs
Pesticides
Basic Toxicology: Exposure-related Concepts
• Persistence
• Bioconcentration
• Transient exposures
Basic Toxicology
Toxicity-related Concepts: specific
processes disrupted by neurodevelopmental toxicants
proliferation
radiation, ethanol, mercury,
cholinesterase inhibitors
migration
radiation, mercury, ethanol
differentiation
ethanol, nicotine, mercury, lead
synaptogenesis
radiation, ethanol, lead, triethyl tin,
parathion, PCBs
gliogenesis &
myelinization
dec. thyroid, ethanol, lead
apoptosis
signaling
ethanol, lead, mercury
ethanol, cholinesterase inhibitors,
mercury, lead, PCBs
Basic Toxicology
Neurodevelopmental Toxicants:
The State of Knowledge
• Only 12 chemicals tested for
neurodevelopmental toxicity according to
current EPA guidelines.
• Extensive data on effects of lead, mercury,
polychlorinated biphenyls (PCBs), alcohol,
nicotine.
• Less extensive but substantial data on
neurotoxic pesticides, solvents other than
alcohol.
• Still fewer data on other compounds including
manganese, fluoride.
Problem: Most data obtained for a few
chemicals. No data available for majority.
EXPOSURE – blood lead, ug/dl
DECLINING
lead
THRESHOLD OF HARM - LEAD
100
REPORTED
HARM
10
1
0.1
1960
1970
1980
1990
2000
YEAR REPORTED
Note: Exposures expressed in micrograms/deciliter (blood le
The Significance of Small Effects:
EFFECTS OF A SMALL SHIFT IN IQ DISTRIBUTION IN A
POPULATION OF 260 MILLION
mean 100
6.0 million
"gifted"
6.0 million
"mentally retarded"
40
80
60
70
100
I.Q.
120
140
130
160
5 Point Decrease in Mean IQ
mean 95
57% INCREASE
IN
"Mentally
Retarded”
Population
2.4 million
"gifted"
9.4 million
"mentally retarded"
40
80
60
70
100
I.Q.
120
140
130
160
Lead
Effects of Lead
on Cognitive and Behavioral Traits
ADHD
LD
hyperactivity
reading, math
impulsivity
spelling
distractibility
pattern recognition
dif. w. instructs word recognition
conduct problems
executive function
attention/vigilance
social skills
OTHER
fine motor
visual motor
aggressive
antisocial
off-task
Percent
Association of Teacher Ratings
With Student Lead Burden
Class Distractible Nonpersistent Dependent Not
Organized
Class
1
2
3
4
5
6
Dentine Lead (ppm)
<5.1
5.1-8.1
8.2-11.8
11.9-17.1
17.2-27.0
>27
Class
Blood Lead,
(micrograms/dl)
7-10
11-12
13-16
17-32
Hyperactive Impulsive
Percent
1
2
3
4
Class Distracted
Persist
Work
Disorganized Hyperactive Impulsive
Independent Organized
Lead
Blood lead levels in the U.S. population 1976 -1999
NHANES II, III, 99+
18
Blood lead levels (mg/dL)
16
14
12
10
8
6
4
2
0
1974 1976 1978 1980 1982 1984 1986 1988 1990
Year
1992
1994 1996 1998
2000
An Overview of Mercury
Dry Deposition
Combustion
Wet
Deposition
Industry & Incinerators
Farming
Runoff
WasteWater
Releases
Volatilization
Pesticides
Fertilizers
Rain & Streams
Hg to HgCH3
to Groundwater
Methylation
to Streams, lakes,
vegetation, soil
Particulates
& Vapor
Volcanoes
Landfills
Groundwater Flow
Sedimentation
Bioaccumulation in Fish
Mercury
Mercury
Effects of Higher Dose Prenatal Exposure
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Mental retardation
Seizures
Cerebral palsy
Disturbances of vision, hearing, sensation
Abnormal gait
Abnormal speech
Disturbances of swallowing and sucking
Abnormal reflexes
Mercury:
Declining Threshold of Harm
(micrograms/kg/day Hg)
DAILY INTAKE
100
Level associated with
harmful effect
Regulatory standard
(maximum safe exposure or high
end exposure from allowed fish
contamination)
10
1
FDA
WHO
ATSDR
0.1
EPA
0.01
1970
1980
1990
YEAR
2000
Mercury
Effects of Low Dose Prenatal Exposure
% Children
children with low test
Per cent of with
7 years
at age
7 years
at age
scores
lowestscores
Percent of Children with Low Scores
Children with low prenatal
mercury
<<
15 15
mg/l
exposure 40
15-30mg/l
15-300
mg/l
30-50
30-50
Children with high prenatal
mercury
> 50 >50
mg/l
µg/l
exposure
30
20
10
0
LANGUAGE
ATTENTION
MOTOR
Source: Grandjean, et. al., "Cognitive Deficit in 7-yearOld Children with Prenatal Exposure to Methylmercury",
Neurotoxicology and Teratology, Vol. 19, No. 6, 1997
VISUOSPATIAL
MEMORY
Figure shows prenatal mercury exposure levels of Faroese children with scores in
the lowest quartile after adjustment for cofounders. For each of the five major
cognitive functions, one neuropsychological test with a high psychometric validity
Mercury
Mercury Exposures
Advised Exposure Limit
• EPA Reference Dose (“safe” upper limit) –
0.1 microgram/kilogram/day
• Equivalent consumption limit
• Women: 1.5 oz. swordfish or 7 oz.
tuna/week
• Child: 1 oz. tuna per 20 lb. body
weight/week
Mercury
Mercury Exposures
Current exposures
• >10% of women of reproductive age
exceed Reference Dose (RfD)
• 50% of women who eat fish exceed
RfD on any given day
• Higher risk: Subsistence fishers,
immigrants, Native Americans
PCBs
From Factory to the Fetus
Dioxins and PCBs: Pathways of Exposure
and Neurodevelopmental Effects
Dioxins:
PVC Manufacturing
Medical/Municipal
Incinerators
Dioxins
PCBs
AIR
SOIL
WATER
FOOD
PCBs:
Transformers
Landfills
Hazardous
Waste Sites
Full-Scale IQ
PCBs
Prenatal Exposure to Polychlorinated Biphenyls
(PCBs) ug/g of fat
Reading Mastery -Word
Comprehension
PCBs
Prenatal Exposure to Polychlorinated Biphenyls
(PCBs) ug/g of fat
PCBs
PCBs: PERVASIVE
DEVELOPMENTAL EFFECTS
Infant
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Birth weight
Head circumference
Gestational age
Performance on Brazelton Neonatal Behavioral
Assessment (BNBA) - motor immaturity, poor
lability, startle
PCBs: PERVASIVE
DEVELOPMENTAL EFFECTS
Early Childhood
• Memory, attention, verbal ability, information
processing
• Psychomotor development
• Sustained activity, high level play
• Withdrawn, depressed behavior
• Hyperactivity
Preteen
• Word and reading comprehension
• Full scale and verbal IQ
• Memory and attention
PCBs: Inadequate Margin of Safety
PCB
BLOOD LEVELS
(ppb)
REPORTED
HUMAN
EXPOSURES
Great Lakes
fish eaters
Great Lakes
non-fish eaters
Midwest and
Northeast US women
Michigan mothers
North Carolina mothers
Wisconsin women
20
REPORTED
HEALTH EFFECTS
IN OFFSPRING
15
10
Decreased reflexes, memory, IQ,
attention, & visual discrimination
5
Dutch mothers
0
Decreased attention, cognitive ability,
high level play, & psychomotor
development;
Increased withdrawn/depressed,
increased hyperactivity.
PCBs
PCB Effects on Thyroid Hormone
• Altered thyroid hormone
Mothers:
Thyroid Hormone,
Thyroid Stimulating
Hormone (TSH)
Infants:
Thyroid Hormone, TSH
Seals and Rats: Thyroid Hormone
• Developmental Implications
Elevated maternal TSH during pregnancy, with or
without reductions of thyroid hormone,
associated with reduced IQ at age 7-9 yrs.
PCBs
PCB Neurodevelopmental Effects:
Possible Mechanisms
• Altered neurotransmitter levels
• Ah receptor mediated effects (dioxin-like
PCBs)
Disruption of production of growth factors and hormones
including enzyme induction, modulation of growth factors,
hormones
• Interference with thyroid hormone
 metabolism through enzyme induction
 interference with thyroid-hormone-mediated gene
transcription
 displacement of thyroxin from carrier protein
Organohalogen Compounds in Breast
Milk in Sweden
4.5
4.0
PBDE
Total TEQ (PCDD/PCDF/PCB)
PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-pdioxin; PCDF, polychlorinated dibenzofuran;
PBDE, polybromonated diphenylether; TEQ, toxic equiv.
120
100
3.5
80
2.5
60
2.0
1.5
40
1.0
20
0.5
0.0
1970
1975
1980
1985
1990
Year
1995
2000
0
2005
TEQ (pg/g fat)
PBDE (ng/g fat)
3.0
PBDE Levels in Humans
35
California (fat)
Sweden (serum)
Germany (whole blood)
Canada (milk)
Finland (milk)
Japan (milk)
Sweden (milk)
PBDE-47 Concentration
(ng/g fat)
30
25
20
15
10
5
0
1981
1983
1985
1987
1990
1992
1994
Year
PBDE, polybrominated diphenylethers. (She et al., 2001)
1996
1998
2000