LETTER TO THE EDITOR

Baby Hair, Mercury Toxicity and Autism

Judith K. Grether,1 Lisa A. Croen,2 and Cheryl A. Theis1

QUERY SHEET

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 LETTER TO THE EDITOR
Baby Hair, Mercury Toxicity and Autism
Judith K. Grether,1 Lisa A. Croen,2 and Cheryl A. Theis1
1
Environmental Health Investigations Branch, California Department of Health Services,
5 Oakland, California, USA
Q1 2
Northern California Kaiser-Permanente Division of Research
Concerns continue to be raised regarding the potential role of
mercury exposure in the etiology of autism. In a recent arti-
cle published in this journal (Reduced Levels of Mercury in
10 First Baby Haircuts of Autistic Children), Holmes, Blaxill, and
Haley (2003) report intriguing findings of higher reported mer-
cury exposure but lower mercury levels in baby hair of children
with autism compared to control children and in children with
severe autism compared to those more mildly affected. At least
15 five interesting, testable hypotheses can be derived from the
Holmes et al. report.
H1: Low hair mercury concentration is a reliable and valid mea-
sure of impaired excretion capability in young children.
H2: Impaired ability to excrete mercury in some children may,
20 in the presence of mercury exposure, contribute to the de-
velopment of autism.
H3: The greater the impairment in excretion, the more severe
the autism.
H4: Autistic children have normal mercury excretion but have
25 a lowered uptake in first baby hair.
H5: Study bias or chance account for the findings in this study.
To our knowledge, the relationship of mercury concentra-
tion in hair to overall excretion capability in infants and young
children has not been established. High hair levels are consid-
30 ered markers of high methylmercury exposure, at least in adults
(Grandjean, welhe, and Nielsen 1994). High maternal hair lev-
els of methylmercury at delivery have been associated with neu-
ropsychological deficits in their young children and high levels
in hair of 7-year-old children were associated with subtle deficits
35 in performance (Grandjean, welhe, and white 1997), (Grandjean
Received ; accepted .
Q2 Address correspondence to Judith K. Grether, PhD, Environmental
Health Investigations Branch, California Department of Health Ser-
vices, 1515 Clay Street, 17th Floor, Oakland, CA 94612, USA. E-mail:
jgrether@dhs.ca.gov
International Journal of Toxicology, 23:13, 2004
Copyright
c American College of Toxicology
ISSN: 1091-5818 print / 1092-874X online
DOI: 10.1080/10915810490502087
et al. 1999; Weihe et al. 2002). While it is possible that excretion
in infants and very young children follows a different biologic
trajectory than in older children and adults, the interpretation
put forward by Holmes et al. of their unexpected findings re-
quires confirmation in a study specifically designed to test this 40
hypothesis.
As acknowledged by Holmes and colleagues, their study had
several methodological limitations that might explain the sur-
prising findings. Both the case and control groups represent
convenience samples that undoubtedly bias the findings to an 45
unknown extent. The children with autism were referrals to the
lead author who is an advocate for chelation therapy for chil-
dren with autism. Although the overall gender pattern among
the children with autism in the study is consistent with the lit-
erature, the high percentage of females in the mildly affected 50
case group is contrary to available data from numerous sources
that consistently show increasing imbalance in the sex ratio with
decreasing severity of impairment. Similarly, controls were re-
cruited through autism parent groups and autism newsletters and
are unlikely to be representative of the population of typically 55
developing children.
As reported in the article, the data collection methods may
also have introduced further bias. Interviews with parents were
conducted by the lead author, ASH, who was not blinded to
the study hypothesis nor to the diagnostic status of the chil- 60
dren. It is not stated if study respondents were kept blinded to
the hypothesis, but this seems unlikely since parents of affected
children had sought the lead authors help for evaluation of mer-
cury toxicity in their children. This raises the possibility that
respondents knew what the study was about and may have re- 65
sponded accordingly. Of further concern, Holmes et al. found
that 46% of mothers in their case group reported being treated
with Rho D immunoglobulin during pregnancy, a strikingly in-
creased proportion compared to the control group and to pop-
ulation estimates. Rho D immunoglobulin contained the ethyl 70
mercury preservative, thimerosal, until late in the 1990s and the
authors interpret their case-control difference as indicating that
1
 2 J. K. GRETHER ET AL.
Rho D immunoglobulin treatment is a risk factor for autism.
Alternatively, the findings could indicate substantial recall bias
75 in maternal reports (which were not validated through review of
medical records) and/or a highly selected and unrepresentative
group of cases. The authors also report that maternal dietary con-
sumption of fish was not significantly associated with autism in
their study. This is surprising given that maternal fish consump-
80 tion during pregnancy is typically the source of greatest prenatal
mercury exposure.
The study also raises concerns related to specimen gathering,
processing, and laboratory analysis. Under the best of circum-
stances, analysis of hair samples is a highly imperfect method-
85 ology for measuring past exposures to metals. Unfortunately,
sometimes it is the only available way to obtain such data. An
expert panel on hair analysis convened by the federal Agency
for Toxic Substances and Disease Registry (ATSDR) in 2001 re-
ported that the lack of standard procedures for collecting, wash-
90 ing, and analyzing hair samples presents notable limitations in
using hair samples in etiologic studies (ASTDR 2003). Holmes
et al. reported that the laboratory testing was conducted in a
blinded fashion but it is not clear that the specimens were sub-
mitted to the laboratory during the same time period and thus
95 randomly analyzed. Without further information to evaluate this
possibility, we are concerned that the observed differences be-
tween mercury levels in specimens from case and control sub-
jects could be due to variability over time in laboratory analysis.
Whether or not the degree of bias introduced by these limi-
100 tations is sufficient to invalidate the provocative findings of this
study can only be determined by further study. An adequate
test of the hypothesis that impaired capability to excrete mer-
cury contributes to autism would require population-based case
RESPONSE
Sound and Fury, Signifying Nothing
105
Mark F. Blaxill,1 Boyd E. Haley,2 and Amy S. Holmes3
1
Safe Minds,
2
University of Kentucky
3
Q3
110
Grether and colleagues raise three types of concern with re-
spect to our study of mercury levels in baby hair of autistic
children. In order, these include (1) issues of logic and fact, (2)
methodological limitations of our study, and (3) political impli-
cations of our findings.
Received ; accepted .
Address correspondence to Mark F. Blaxill, Safe Minds,
and control groups and data collection methods that minimize 115
recall and reporting biases. For evaluation of first baby hair, the
concern about lack of standardization in collection procedures
can probably only be solved in a prospective study that enrolls
baby sibs of ASD-affected and typically developing children.
Other concerns about laboratory analyses can be alleviated by 120
use of research rather than commercial laboratories and by as-
suring that case and control specimens are randomly and blindly
analyzed. Research on etiology of autism is, unfortunately, still
in very early stages and we dont yet have sufficient answers
to guide prevention and medical treatment. We urge caution in 125
acceptance of the conclusions of this interesting study and join
with the authors in calling for additional, rigorously designed,
research to replicate the findings.
REFERENCES
Agency for Toxic Substances and Disease Registry (ATSDR). 2003. Analysis of 130
hair samples: How do hair sampling results relate to environmental exposures?
online report http://www.atsdr.cdc.gov/HAC/hair analysis/.
Grandjean, P., P. Welhe, and J. B. Nielsen. 1994. Methylmercury: Significance
of intrauterine and postnatal exposures. Clin. Chem. 40:13951400.
Grandjean, P., P. Welhe, and R. White. 1997. Cognitive deficit in 7-year-old chil- 135
dren with prenatal exposure to methylmercury. Neurotoxicol. Teratol. 19:417
428.
Grandjean, P., E. Budtz-Jorgensen, R. F. White, P. J. Jorgensen, P. Weihe, F.
Debes, and N. Keiding. 1999. Methylmercury exposure biomarkers as indica-
tors of neurotoxicity in children aged 7 years. Am. J. Epidemiol. 150:301305. 140
Holmes, A. S., M. F. Blaxill, and B. E. Haley. 2003. Reduced levels of mercury
in first baby haircuts of autistic children. Int. J. Toxicol. 22:277285.
Weihe, P., J. C. Hansen, K. Murata, F. Debes, P. Jorgensen, U. Steuerwald, R. F.
White, and P. Grandjean. 2002. Neurobehavioral performance of Inuit chil-
dren with increased prenatal exposure to methylmercury. Int. J. Circumpolar 145
Health. 61:4149.
Our analysis demonstrated a marked departure from the null hy-
pothesis of no difference between first baby haircut mercury
levels in autistic and control children. Grether and her col-
leagues offer five hypotheses with which to test our data, two of 150
whichH2 and H3are consistent with our interpretation, two
of whichH1 and H4suggest different interpretations, and
oneH5that dismisses our analysis out of hand. Although
wed have been intrigued to hear them defend the fourth, they
 LETTER TO THE EDITOR
155 focused their substantive attention only on the first, which is not
even a valid hypothesis and based on a logical error. Contrary
to their suggestion, low mercury hair concentration can provide
a reliable and valid measure of impaired excretion capability
only when maternal mercury exposure is high enough to warrant
160 an expectation of high mercury levels in hair. We welcome tests
of our arguments, but only when they reflect an understanding
of our work, an understanding not demonstrated here.
Grether and colleagues also question the validity of the con-
nection between infant hair mercury levels and mercury excre-
165 tion, claiming that such a connection has not been established.
We strongly support additional research on infant mercury ex-
cretion. But the small amount of work that has been done is con-
sistent with our findings and interpretations. One research group
has reported preliminary findings in autistic hair samples con-
170 sistent with ours.1 In addition, Faeroe Island researchers have
shown that higher infant hair mercury levels were associated
with faster progress to developmental milestones.2 This finding
puzzled the researchers, who never considered a differential ex-
cretion hypothesis and assumed that higher hair levels would
175 produce slower development. But the results provide support
for the idea that high mercury hair levels in a high-exposure
population are associated with relatively positive developmen-
tal outcomes.
Next, Grether and colleagues offer additional speculation
180 (H5) on a number of methodological points. Many of these points
reiterate cautions we offered ourselves, including the benefits of
prospective design, careful case and control recruitment to min-
imize any source of potential bias, and the use of research as
opposed to commercial laboratories.
185 Nevertheless, it is very hard to dismiss our findings as a con-
sequence simply of study bias and nearly impossible, statisti-
cally, to dismiss them as chance findings. Perhaps Grether and
colleagues believe we simply fabricated the data (indeed, the
authors hint at a hidden commercial agenda around chelation
190 therapy). We strongly reject any such allegation.
As to more subtle potential biases, we suggest that skeptics of
our findings pay closer attention to our control group findings.
This is the group in which any argument for study bias is at
its weakest. Yet the variance from an expected finding of low
195 dosage is high. In 3 of the 45 normal children, the mercury
concentration in hair was well over 10 ppm, above levels that
would be considered neurotoxic in adult populations,3 and over
1 in 4 had concentrations exceeding 4 ppm. We have responded
to some comments that it is these control results that are most
200 likely to be biased (whereas the autistics samples are closer to
expected outcomes), but where we have seen evidence on normal
infant controls we have found it consistent with our work. One
recent report provided examples of similarly high mercury hair
levels in a California population with high mercury exposures,
including an additional infant mercury hair concentration of over
3
3 ppm (compared to our control mean of 3.63 ppm).4 We look 205
forward to learning the results of ongoing replication efforts and
do not expect that they will reveal material biases in our methods.
Finally, Grether and colleagues reveal their real concerns near
the end of their letter when they profess their preference to in-
validate the findings, largely because they are provocative. In 210
that spirit, they urge caution in the acceptance of [our] conclu-
sions.
We see little scientific benefit in such caution. If increased
mercury exposure is indeed implicated in the increases in autism
rates, then the investigation into the mechanism of action and 215
potential treatments must proceed with a sense of urgency and
a bias to action. Autism rates have reached disturbing levels
in recent years and large numbers of children may have been
affected by increased mercury exposure and/or retention. Of-
fering false comfort in the guise of weak hypotheses does little 220
more than divert resources and attention away from this large
emerging population. We note with disappointment that Grether
and Croen have sponsored similar diversionary tactics before.
In a recent publication, they offered what they would probably
consider a less provocative hypotheses, in this case the sugges- 225
tion that a diagnostic substitution effect might explain recent
autism increases.5 Although this was an explanation they might
have found more comforting, it was simply wrong. Indeed, it
was so clearly flawed that they subsequently withdrew their hy-
pothesis based on analysis they could have performed with their 230
original data.6
For the health and welfare of affected children and their fam-
ilies, we suggest they and others worry less about whether our
conclusions are provocative and more about whether they are
biologically plausible and consistent with other evidence. We 235
strongly encourage investigation of the environmental causes of
autism and urge that only the highest standards of science and
reason be applied when developing and disseminating hypothe-
ses for scientific work.
REFERENCES 240
1. Hu, L-W., J. A. Bernard, and J. Che. 2003. Neutron activation analysis of
hair samples for the identification of autism. Transactions of the American
Nuclear Society 89: Q4
2. Grandjean, P., P. Weihe, and R. F. White. 1995. Milestone development in
infants exposed to methylmercury from human milk. Neurotoxicology 16:27 245
33.
3. National Academy of Science. 2000. Toxicological effect of methylmercury.
National Academy Press: Washington, DC.
4. Hightower, J. M., and D. Moore. 2003. Mercury levels in high-end consumers
of fish. Environ. Health Perspect. 111:604608. 250
5. Croen, L. A., J. K. Grether, J. Hoogstrate, and S. Selvin. 2002. The changing
prevalence of autism in California. J. Autism. Dev. Disord. 32:207215.
6. Croen, L. A., and J. K. Grether. 2003. Response: A response to Blaxill, Baskin
and Spitzer on Croen et al. (2002). The changing prevalence of autism in
California. J. Autism. Dev. Disord. 33:227229. 255