Claudia S. Miller, M.D., M.S.Professor, Family & Community Medicine
The University of Texas Health Science Center at San Antonio
Synthetic Organic Chemical ProductionUnited States, 1945 - 1985
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Our Boxes:
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• Workplace
• School
• Vehicles
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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 re-uptake 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
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Neurodevelopmental toxicity Acetylcholinesterase inhibitionOxidative stress
Neurodevelopmental toxicity
CYP 3A4CYP 2B6(polymorphic) PON1
(polymorphic)
Parent Compound
Phase IIDetoxification
Phase IDetoxification Reactive Intermediate
Free sulfur atoms inactivate CYP3A4
CYP3A4 cannot metabolize testosterone
Endocrine disruption— hypermasculinity
1 2 3
Chlorpyrifos Detoxification
Impact of Xenobiotic Exposures on
Neurodevelopment
Relationship between TILT, Addiction and Abdiction
TILT(Loss of Tolerance)
Avoid Withdrawal(2 strategies)
Avoid substancealtogether
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)
0
5
10
15
20
25
30
35
40
45
% ControlAutism
P < .04
P < .05
P < .003
Pesticide exposure
Chemical exposure
Vaccinatedwhile pregnant
ReceivedRhogamfor Rh incompatibilty
ns
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 DifferencesBetween Autism Cases and Controls
0
5
10
15
20
25
30
35
% ControlAutismP < .04
P < .05
ns
Antibiotic use
Reaction tovaccination
Received nochildhood vaccinations
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)
0
5
10
15
20
25
30
35
40
Control
ADHD
ASD
P=.001 P=.002 P=.030
Symptoms Chemicalintolerances
Other exposures
Comparison of Food Allergies/Intolerancesand Food Preferences/Cravings Between
ASD (n=280), ADHD (n=147) and Controls (n=149)
0
10
20
30
40
50
60
70
%ControlADHDASD
Food allergies/sensitivities
Food preferences/cravings
QEESI Score Comparisons Between Autism (n=187), ADHD (n=147) and Controls (n=149)
0
5
10
15
20
25
30
35
40
Control
ADHD
Autism
P=.001 P=.004 P=.033
Symptoms Chemical intolerances
Other exposures
Comparison of Food Allergies/Intolerancesand Food Preferences/Cravings Between
Autism (n=187), ADHD (n=147) and Controls (n=149)
0
10
20
30
40
50
60
70
% ControlADHDAutism
Food Allergies/sensitivities
Food Preferences/cravings
Autism and ADHD differ significantly (P<.001) from Control but not from each other.
Autism differs significantly from Control and ADHD(P<.001),