[Pharmwaste] Environmental Chemicals: Evaluating Low-Dose Effects

DeBiasi, Deborah (DEQ) Deborah.DeBiasi at deq.virginia.gov
Thu Mar 15 11:45:00 EDT 2012


http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179

 

Environmental Chemicals: Evaluating Low-Dose Effects

Linda S. Birnbaum

Director, NIEHS and NTP, National Institutes of Health, Department of
Health and Human Services, Research Triangle Park, North Carolina,
E-mail: birnbaumls at niehs.nih.gov

Citation: Birnbaum LS 2012. Environmental Chemicals: Evaluating Low-Dose
Effects. Environ Health Perspect 120:a143-a144.
http://dx.doi.org/10.1289/ehp.1205179

Online: 14 March 2012

Linda S. Birnbaum, director of the NIEHS and the NTP, oversees a budget
that funds multidisciplinary biomedical research programs and prevention
and intervention efforts that encompass training, education, technology
transfer, and community outreach. She recently received an honorary
Doctor of Science from the University of Rochester, the distinguished
alumna award from the University of Illinois, and was elected to the
Institute of Medicine. She is the author of > 700 peer-reviewed
publications, book chapters, abstracts, and reports. Birnbaum received
her M.S. and Ph.D. in microbiology from the University of Illinois,
Urbana. A board-certified toxicologist, she has served as a federal
scientist for 31 years, 19 with the U.S. EPA Office of Research and
Development, preceded by 10 years at the NIEHS as a senior staff fellow,
a principal investigator, a research microbiologist, and a group leader
for the institute's Chemical Disposition Group.

The author declares she has no actual or potential competing financial
interests.

 

Around the world, large-scale biomonitoring programs have provided
extensive information about human exposure to a large number of
environmental chemicals (Barr et al. 2010
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
1> ; Bilau et al. 2008
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
2> ; Churchill et al. 2001
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
5> ; Woodruff et al. 2011
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
14> ). As these programs extend to look at vulnerable populations,
including pregnant women, fetuses, and the elderly, our knowledge of the
widespread distribution of many of these chemicals-including hundreds
that have been classified as endocrine disruptors-continues to climb.
However, the mere presence of a chemical in humans is not necessarily
cause for concern. What is concerning is the increasing number of
epidemiological studies showing associations between the concentration
of these chemicals in the general population and adverse health end
points (Braun and Hauser 2011
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
3> ; Crain et al. 2008
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
6> ). Although high exposures following accidental or occupational
exposures to endocrine disruptors, industrial chemicals, pesticides, and
pharmaceuticals have shown striking effects, epidemiological studies
suggest that low doses may also be unsafe, even for populations that are
not typically considered "vulnerable."

Making connections between the exposome and risk assessment is a
difficult but important venture (Paustenbach and Galbraith 2006
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
10> ; Rappaport and Smith 2010
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
11> ). Risk assessments typically examine the effects of high doses of
administered chemicals to determine the lowest observed adverse effect
levels (LOAELs) and no observed adverse effect levels (NOAELs);
reference doses, which are assumed safe for human exposure, are then
calculated from these doses using a number of safety factors. Thus,
human exposures to thousands of environmental chemicals fall in the
range of nonnegligible doses that are thought to be safe from a risk
assessment perspective. Yet the ever-increasing data from human
biomonitoring and epidemiological studies suggests otherwise: Low
internal doses of endocrine disruptors found in typical human
populations have been linked to obesity (Carwile and Michels 2011
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
4> ), infertility (Meeker and Stapleton 2010
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
7> ), neurobehavioral disorders (Swan et al. 2010
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
12> ), and immune dysfunction (Miyashita et al. 2011
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
9> ), among others.

For several decades, environmental health scientists have been dedicated
to addressing the "low-dose hypothesis," which postulates that low doses
of chemicals can have effects that would not necessarily be predicted
from their effects at high doses. More than 10 years ago, a National
Toxicology Program expert panel concluded that there was evidence for
low-dose effects for a select number of well-studied endocrine
disruptors (Melnick et al. 2002
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
8> ). Now, a diverse group of scientists has reexamined this large body
of literature, finding examples of low-dose effects for dozens of
chemicals across a range of chemical classes, including industrial
chemicals, plastic components and plasticizers, pesticides,
phytoestrogens, preservatives, surfactants and detergents, flame
retardants, and sunblock, among others (Vandenberg et al. 2012
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
13> ). Vandenberg et al. selected several examples of controversial
low-dose test cases and applied an analytical weight-of-evidence
approach to determine whether there was sufficient evidence to conclude
that particular environmental chemicals had effects on specific
biological end points. Their analysis addresses how experimental design,
choice of animal strain/species, study size, and inclusion of
appropriate controls affect the outcome and interpretation of studies on
bisphenol A (BPA), atrazine, dioxin, and perchlorate. Their study
provides important insight into the effects of environmental chemicals
on health-related end points and addresses the mechanistic questions of
how chemicals with hormonal activity can have effects at external doses
that are often considered safe by the regulatory community.

Vandenberg et al. (2012)
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
13>  have also collected several hundred examples of nonmonotonic
dose-response curves (representing many classes of environmental
chemicals) that have been observed in cultured cells, animals, and even
human populations (Vandenberg et al. 2012
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#r
13> ). Most importantly, they reviewed the voluminous endocrine
literature on how and why nonlinear responses manifest at different
levels of biological complexity, including the combination of competing
monotonic responses (such as enhanced cell proliferation and
cytotoxicity), the expression of cell- and tissue-specific cofactors and
receptors, and receptor down-regulation, desensitization, and
competition. Thus, the question is no longer whether nonmonotonic dose
responses are "real" and occur frequently enough to be a concern;
clearly these are common phenomena with well-understood mechanisms.
Instead, the question is which dose-response shapes should be expected
for specific environmental chemicals and under what specific
circumstances.

Moving forward, studies of suspected endocrine disruptors need to
include doses that result in relevant internal human levels and examine
a wide range of biological end points. Dose-response studies should
include a range of doses to distinguish between linear monotonic and
nonmonotonic responses. Nonlinear relationships should not be dismissed.
Collaborations between research scientists in academia, government, and
industry should be encouraged to allow for development of more
sophisticated study designs to facilitate regulatory decisions. It is
time to start the conversation between environmental health scientists,
toxicologists, and risk assessors to determine how our understanding of
low-dose effects and nonmonotonic dose responses influence the way risk
assessments are performed for chemicals with endocrine-disrupting
activities. Together, we can take appropriate actions to protect human
and wildlife populations from these harmful chemicals and facilitate
better regulatory decision making.

References Top
<http://ehp03.niehs.nih.gov/article/info%3Adoi%2F10.1289%2Fehp.1205179#t
op> 

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Deborah L. DeBiasi
Email:   Deborah.DeBiasi at deq.virginia.gov
WEB site address:  www.deq.virginia.gov <http://www.deq.virginia.gov/> 
Virginia Department of Environmental Quality
Office of Water Permit and Compliance Assistance Programs
Industrial Pretreatment/Whole Effluent Toxicity (WET) Program
PPCPs, EDCs, and Microconstituents 
http://www.deq.virginia.gov/vpdes/Microconstituents.html

4th National DEA Drug Collection 04/28/12, 10-2 pm 
Go to www.dea.gov for site locations

Mail:          P.O. Box 1105, Richmond, VA  23218
Location:  629 E. Main Street, Richmond, VA  23219
PH:         804-698-4028      FAX:      804-698-4032

 

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