Environmental Exposures and Autism
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Claudia S. Miller, M.D., M.S. Professor, Family & Community Medicine The University of Texas Health Science Center at San Antonio millercs@uthscsa.edu
Synthetic Organic Chemical Production United States, 1945 - 1985
Source: U.S. Intern. Trade Commission
U.S. Pesticide Production, All types, 1927-1988
Source: EPA Market Estimates, 1986, 1988; Pimentel & Andow, 1984; Metcalf, 1980.
90% of Americans Spend 90% of the Day Indoors
Our Boxes:
• • • •
Home Workplace School Vehicles
Mage and Gammage 1985, Evaluation of Changes in Outdoor Air Quality Occurring over the Past Several Decades, In Indoor Air and Human Health. Gammage and Kaye Eds., Chelsea, MI, Lewis Publishers, p. 13)
Historical Development of Ventilation Standards in the U.S.
Evidence for TILT
• • • • •
Similar reports in different regions/countries Complaints of new intolerances for foods, alcohol, caffeine, and medications, not only chemicals Resemblance to addiction Plausible anatomic locus Recent animal models
Diagnosing Chemical and Food Triggers for Autism Using an EMU
Chemical Intolerance – Genotypes
• • • • • •
Canadian case control study to determine whether chemically intolerant individuals differ from controls for genetic polymorphisms in drug-metabolizing enzymes Caucasian female cases (203) and controls (162) CYP2D6, NAT1, NAT2, PON1, PON2, MTHFR were genotyped Significant difference found in cases vs. controls for CYP2D6 (p=0.02) OR CYP2D6 homozygous active=3.36 (p=0.01) OR NAT2 rapid metabolizer=4.14 (p=0.01)
Source: McKeown-Essen et al, Int J Epidemiol 2004; 33:1-8
Chemical Intolerance – Genotypes
•
• •
CPY2D6 metabolizes centrally acting drugs and toxins such as tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, amphetamines, codeine, neuroleptics, neurotoxins, and endogenous neurotransmitters Latter finding may be relevant to observations that poor metabolizers score higher on anxiety scales and lower on socialization scales NAT2 expresses arylamine transferase which determines susceptibility to aromatic amines
Source: McKeown-Essen et al, Int J Epidemiol 2004; 33:1-8
• • • • •
Chemical Intolerance – Genotypes
Cases were more likely to be heterozygous for PON1-55 (OR=2.05, p=0.04) and PON1-192 (OR=1.57, p=0.04) PON genes have been linked to Gulf War veterans’ illnesses (Haley et al., 1999) Post hoc analysis showed significant effect of being a rapid metabolizer for both NAT2 and CYP2D6: OR for rapid/rapid vs. slow/slow combination of CYP2D6 and NAT2 was 18.7 Other studies: Binkley et al., 2001 showed higher prevalence of cholecystokinin B receptor allele 7 compared with controls Conclusion: chemically intolerant individuals differ from controls for genetic polymorphisms in enzymes that metabolize drugs/toxins/endogenous neurotransmitters
Source: McKeown-Essen et al, Int J Epidemiol 2004; 33:1-8
Chlorpyrifos Detoxification
Parent Compound
S P
H3C O O N CH3 CI CI CI O
Phase I Detoxification
Reactive Intermediate
CI
Phase II Detoxification
O P
O
[S] +
CYP 3A4 CYP 2B6(polymorphic)
H3C
O
O N CH3 CI CI
Elimination
PON1 (polymorphic)
Chlorpyrifos
Chlorpyrifos-oxon
1
•Neurodevelopmental toxicity
2
3
•Free sulfur atoms •Acetylcholinesterase inhibition •Oxidative stress inactivate CYP3A4 •CYP3A4 cannot •Neurodevelopmental toxicity metabolize testosterone •Endocrine disruption— hypermasculinity
Impact of Xenobiotic Exposures on Neurodevelopment
Relationship between TILT, Addiction and Abdiction
TILT (Loss of Tolerance)
Avoid Withdrawal (2 strategies)
Avoid substance altogether
Take substance regularly
Abdiction
Addiction
High validity, reliability Sensitivity 92%, specificity 95% Symptom scale derived by factor analysis “Symptom star”
(Miller and Prihoda, Tox Industr Health 15:370-385, 1999)
http://familymed.uthscsa.edu/ queesi.pdf
• Online Autism Survey http://familymed.uthscsa.edu/autismsurvey/ • Currently over 400 participants – Family histories – Environmental exposures – Chemical intolerances
Environmental Exposures During Pregnancy Autism cases (n = 210 children) and Controls (n = 369 children)
45 40 35 30
P < .04 P < .05
%
25 20 15 10 5 0
Pesticide exposure Chemical exposure
P < .003 ns
Control Autism
Vaccinate d while pregnant
Received Rhogam for Rh incompatibilty
Did you use pesticides, herbicides or have pest control services during your pregnancy? Were you exposed to fumes/chemicals (such as paint and refinishing products or new carpet, etc.) on the job or at home during your pregnancy?
Medical/Health Care Differences Between Autism Cases and Controls
35 30 25 20 15 10
ns P < .04 P < .05
%
Control Autism
5 0
Reaction to vaccination Received no childhood vaccinations
Antibiotic use
Multiple infections requiring prolonged use of antibiotics Reactions to vaccinations that prompted a call to the doctor
Maternal QEESI Score Comparisons Between ASD (n=280), ADHD (n=147) and Controls (n=149)
P=.001 P=.002 P=.030
40 35 30 25 20 15 10 5 0
Symptoms Chemical intolerances Other exposures
Control ADHD ASD
Comparison of Food Allergies/Intolerances and Food Preferences/Cravings Between ASD (n=280), ADHD (n=147) and Controls (n=149)
70 60 50 40 30 20 10 0
Food allergies/ sensitivities Food preferences/ cravings
%
Control ADHD ASD
QEESI Score Comparisons Between Autism (n=187), ADHD (n=147) and Controls (n=149)
P=.001 P=.004 P=.033
40 35 30 25 20 15 10 5 0
Symptoms Chemical intolerances Other exposures
Control ADHD Autism
Comparison of Food Allergies/Intolerances and Food Preferences/Cravings Between Autism (n=187), ADHD (n=147) and Controls (n=149)
70 60 50 40 30 20 10 0
Food Allergies/ sensitivities
Autism differs significantly from Control and ADHD (P<.001),
%
Control ADHD Autism
Food Preferences/ cravings
Autism and ADHD differ significantly (P<.001) from Control but not from each other.
Claudia S. Miller, M.D., M.S. Professor, Family & Community Medicine The University of Texas Health Science Center at San Antonio millercs@uthscsa.edu
Synthetic Organic Chemical Production United States, 1945 - 1985
Source: U.S. Intern. Trade Commission
U.S. Pesticide Production, All types, 1927-1988
Source: EPA Market Estimates, 1986, 1988; Pimentel & Andow, 1984; Metcalf, 1980.
90% of Americans Spend 90% of the Day Indoors
Our Boxes:
• • • •
Home Workplace School Vehicles
Mage and Gammage 1985, Evaluation of Changes in Outdoor Air Quality Occurring over the Past Several Decades, In Indoor Air and Human Health. Gammage and Kaye Eds., Chelsea, MI, Lewis Publishers, p. 13)
Historical Development of Ventilation Standards in the U.S.
Evidence for TILT
• • • • •
Similar reports in different regions/countries Complaints of new intolerances for foods, alcohol, caffeine, and medications, not only chemicals Resemblance to addiction Plausible anatomic locus Recent animal models
Diagnosing Chemical and Food Triggers for Autism Using an EMU
Chemical Intolerance – Genotypes
• • • • • •
Canadian case control study to determine whether chemically intolerant individuals differ from controls for genetic polymorphisms in drug-metabolizing enzymes Caucasian female cases (203) and controls (162) CYP2D6, NAT1, NAT2, PON1, PON2, MTHFR were genotyped Significant difference found in cases vs. controls for CYP2D6 (p=0.02) OR CYP2D6 homozygous active=3.36 (p=0.01) OR NAT2 rapid metabolizer=4.14 (p=0.01)
Source: McKeown-Essen et al, Int J Epidemiol 2004; 33:1-8
Chemical Intolerance – Genotypes
•
• •
CPY2D6 metabolizes centrally acting drugs and toxins such as tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, amphetamines, codeine, neuroleptics, neurotoxins, and endogenous neurotransmitters Latter finding may be relevant to observations that poor metabolizers score higher on anxiety scales and lower on socialization scales NAT2 expresses arylamine transferase which determines susceptibility to aromatic amines
Source: McKeown-Essen et al, Int J Epidemiol 2004; 33:1-8
• • • • •
Chemical Intolerance – Genotypes
Cases were more likely to be heterozygous for PON1-55 (OR=2.05, p=0.04) and PON1-192 (OR=1.57, p=0.04) PON genes have been linked to Gulf War veterans’ illnesses (Haley et al., 1999) Post hoc analysis showed significant effect of being a rapid metabolizer for both NAT2 and CYP2D6: OR for rapid/rapid vs. slow/slow combination of CYP2D6 and NAT2 was 18.7 Other studies: Binkley et al., 2001 showed higher prevalence of cholecystokinin B receptor allele 7 compared with controls Conclusion: chemically intolerant individuals differ from controls for genetic polymorphisms in enzymes that metabolize drugs/toxins/endogenous neurotransmitters
Source: McKeown-Essen et al, Int J Epidemiol 2004; 33:1-8
Chlorpyrifos Detoxification
Parent Compound
S P
H3C O O N CH3 CI CI CI O
Phase I Detoxification
Reactive Intermediate
CI
Phase II Detoxification
O P
O
[S] +
CYP 3A4 CYP 2B6(polymorphic)
H3C
O
O N CH3 CI CI
Elimination
PON1 (polymorphic)
Chlorpyrifos
Chlorpyrifos-oxon
1
•Neurodevelopmental toxicity
2
3
•Free sulfur atoms •Acetylcholinesterase inhibition •Oxidative stress inactivate CYP3A4 •CYP3A4 cannot •Neurodevelopmental toxicity metabolize testosterone •Endocrine disruption— hypermasculinity
Impact of Xenobiotic Exposures on Neurodevelopment
Relationship between TILT, Addiction and Abdiction
TILT (Loss of Tolerance)
Avoid Withdrawal (2 strategies)
Avoid substance altogether
Take substance regularly
Abdiction
Addiction
High validity, reliability Sensitivity 92%, specificity 95% Symptom scale derived by factor analysis “Symptom star”
(Miller and Prihoda, Tox Industr Health 15:370-385, 1999)
http://familymed.uthscsa.edu/ queesi.pdf
• Online Autism Survey http://familymed.uthscsa.edu/autismsurvey/ • Currently over 400 participants – Family histories – Environmental exposures – Chemical intolerances
Environmental Exposures During Pregnancy Autism cases (n = 210 children) and Controls (n = 369 children)
45 40 35 30
P < .04 P < .05
%
25 20 15 10 5 0
Pesticide exposure Chemical exposure
P < .003 ns
Control Autism
Vaccinate d while pregnant
Received Rhogam for Rh incompatibilty
Did you use pesticides, herbicides or have pest control services during your pregnancy? Were you exposed to fumes/chemicals (such as paint and refinishing products or new carpet, etc.) on the job or at home during your pregnancy?
Medical/Health Care Differences Between Autism Cases and Controls
35 30 25 20 15 10
ns P < .04 P < .05
%
Control Autism
5 0
Reaction to vaccination Received no childhood vaccinations
Antibiotic use
Multiple infections requiring prolonged use of antibiotics Reactions to vaccinations that prompted a call to the doctor
Maternal QEESI Score Comparisons Between ASD (n=280), ADHD (n=147) and Controls (n=149)
P=.001 P=.002 P=.030
40 35 30 25 20 15 10 5 0
Symptoms Chemical intolerances Other exposures
Control ADHD ASD
Comparison of Food Allergies/Intolerances and Food Preferences/Cravings Between ASD (n=280), ADHD (n=147) and Controls (n=149)
70 60 50 40 30 20 10 0
Food allergies/ sensitivities Food preferences/ cravings
%
Control ADHD ASD
QEESI Score Comparisons Between Autism (n=187), ADHD (n=147) and Controls (n=149)
P=.001 P=.004 P=.033
40 35 30 25 20 15 10 5 0
Symptoms Chemical intolerances Other exposures
Control ADHD Autism
Comparison of Food Allergies/Intolerances and Food Preferences/Cravings Between Autism (n=187), ADHD (n=147) and Controls (n=149)
70 60 50 40 30 20 10 0
Food Allergies/ sensitivities
Autism differs significantly from Control and ADHD (P<.001),
%
Control ADHD Autism
Food Preferences/ cravings
Autism and ADHD differ significantly (P<.001) from Control but not from each other.
