EHP~Applying Research to Public Health Questions: Timing and the Environmentally

[Guest guest]

" NIEHS researchers are turning their attention to the “environmentally

relevant dose,†which is the dose in the range of typical human exposure

as measured in tissue, blood, and urine of study subjects. Simply put, the

environmentally relevant dose is based on the internal concentration of the

toxicant rather than the administered dose. "

I

Applying Research to Public Health Questions: Timing and the

Environmentally Relevant Dose

Environ Health Perspect. doi:10.1289/ehp.0901417 available via

_http://dx.doi.org_ (http://dx.doi.org/) [Online 26 October 2009]

The mission of National Institute of Environmental Health Sciences (NIEHS)

is to improve the health of the American people by understanding the role

of environmental exposures in disease and dysfunction. We accomplish this

mission by conducting and funding research—including in vitro, animal, and

human studies—on the health effects of environmental agents. Our goal is to

prevent disease by identifying and reducing exposures to environmental

agents that compromise health. It is clear that every complex disease has both

an environmental and a genetic component. Thus, NIEHS-sponsored research

must play an important role in understanding disease etiology. In the last

few years there have been workshops (Melnick et al. 2002; vom Saal et al.

2007), manuscripts (Myers et al. 2009a, 2009b), and even society-position

papers (The Endocrine Society 2009) indicating that increased use of

environmental health science data by policy makers should lead to reductions in

the

human burden of disease.

There are several recent examples of how research supported by the NIEHS

is leading to paradigm shifts in understanding how environmental toxicants—

even at very low-level exposures—can have significant consequences,

including dysfunction and disease. These paradigm shifts are being informed by

new

approaches for dose measurement. NIEHS researchers are turning their

attention to the “environmentally relevant dose,†which is the dose in the

range

of typical human exposure as measured in tissue, blood, and urine of

study subjects. Simply put, the environmentally relevant dose is based on the

internal concentration of the toxicant rather than the administered dose.

In 2007, the NIEHS invited a panel of experts to Chapel Hill, North

Carolina, for a scientific review of all literature published on bisphenol A

(BPA). The expert panel then issued a consensus statement (vom Saal et al.

2007), which concluded that low environmentally relevant doses of BPA could

cause numerous diseases in animal models, and that there was evidence for both

low-dose effects and for nonmonotonic dose–response relationships.

Overall, similar conclusions were reached by the National Toxicology

Program’s

Center for the Evaluation of Risks to Human Reproduction (NTP 2008), which

focused on the developmental and reproductive effects of BPA.

An article in this issue of Environmental Health Perspectives (Myers et

al. 2009b) highlights this discussion of low-dose effects and notes that

nonmonotonic, or biphasic, dose–response curves are commonly observed in

endocrinology. This suggests that high doses may not be appropriate to predict

the safety of low doses when hormonally active or modulating compounds are

studied. Their conclusions are supported by the position statement published

by the Endocrine Society (2009). This debate—whether chemicals with

endocrine-disrupting activity can cause toxicity at environmentally relevant

doses

—has been under way for more than a decade (Melnick et al. 2002). There

are now low-dose data not only on BPA but also on phthalates, polychlorinated

biphenyls (PCBs), dioxins, heavy metals such as lead and mercury,

perchlorate, and some diverse pesticides such as hexachlorobenzene and

atrazine.

Indeed, the doses used in many animal toxicology studies result in internal

concentrations that are in the range of human exposures.

Many of these low-dose studies demonstrate that the timing of exposure is

critical to the outcome and that exposures during early life stages (fetal,

infant, and pubertal) are particularly important. This recognition of

critical windows of vulnerability not only demonstrates the developmental basis

of disease but also that the timing, as well as the dose, makes the

poison.

Understanding the connection between our health and our environment, with

its mixture of chemicals, diet, and lifestyle stressors, is no less complex

than understanding the intricacies of the human genome; just as we have

moved beyond “one gene, one disease,†we must move beyond “one chemical,

one

dose (range), one health outcome.†Reliability and validity are

established in science by replication of findings in multiple independent

studies. A

weight-of- evidence approach is essential in understanding the public

health impacts of environmental exposures.

S. Birnbaum

Director, NIEHS and NTP

National Institutes of Health

Department of Health and Human Services

Research Triangle Park, North Carolina

E-mail: _birnbaumls@..._ (mailto:birnbaumls@...)

S. Birnbaum is director of the NIEHS and the NTP. She oversees a

budget that funds multidisciplinary biomedical research programs, and

prevention and intervention efforts that encompass training, education,

technology

transfer, and community outreach. Birnbaum has received numerous awards,

including the Women in Toxicology Elsevier Mentoring Award, the Society of

Toxicology Public Communications Award, the U.S. Environmental Protection

Agency’s (EPA) Health Science Achievement Award and Diversity Leadership

Award, and 12 Science and Technology Achievement Awards. She is the author of

more than 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 nearly 29 years: 19 years 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

finally as a group leader for the institute’s Chemical Disposition Group.

_http://www.blip.tv/file/2756814/_ (http://www.blip.tv/file/2756814/)