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 ProductionUnited States, 1945 - 1985

Sou

rce

: U

.S.

Inte

rn.

Tra

de C

omm

issi

on

U.S. Pesticide Production,All types, 1927-1988

Sou

rce

: E

PA

Mar

ket

Est

imat

es,

198

6, 1

988;

P

imen

tel &

And

ow,

198

4; M

etca

lf, 1

980.

90% of Americans Spend 90% of the Day Indoors

Our Boxes:

• Home

• Workplace

• School

• Vehicles

Historical Development of Ventilation Standards in the U.S.

Mag

e an

d G

amm

age

1985

, E

valu

atio

n o

f C

han

ges

in O

utdo

or A

ir Q

ual

ity

Occ

urrin

g o

ver

the

Pas

t S

ever

al D

eca

des

, In

Ind

oor

Air

and

Hum

an

Hea

lth.

Gam

mag

e an

d K

aye

Eds

., C

hels

ea,

MI,

Lew

is P

ublis

her

s, p

. 13

)

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

H3CO

SO

O

P

CH3

CI

CI

CI

NElimination

CI

H3CO

OO

O

P

CH3

CI

CI

N[S] +

Chlorpyrifos-oxonChlorpyrifos

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),