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      Meeting Report: Moving Upstream—Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making

      1 , 2 , 3 , 4 , 5 , 6 , 2 , 7 , 3 , 1 , 2 , 8 , 9 , 10 , 11 ,   9 , 4 , 12 , 12 , 9 , 13 , 14 , 9 , 15 , 12 , 16 , 5 , 4 , 17

      Environmental Health Perspectives

      National Institute of Environmental Health Sciences

      adverse health effects, androgen antagonists, hazard identification, immunotoxicants, risk assessment, science policy, thyroid hormone, toxicologic assessments

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          Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an “adverse effect” in the context of hazard identification and risk assessment.


          Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available.


          Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects.


          For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.

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          Most cited references 50

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          Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000.

          We measured the urinary monoester metabolites of seven commonly used phthalates in approximately 2,540 samples collected from participants of the National Health and Nutrition Examination Survey (NHANES), 1999-2000, who were greater than or equal to 6 years of age. We found detectable levels of metabolites monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono-(2-ethylhexyl) phthalate (MEHP) in > 75% of the samples, suggesting widespread exposure in the United States to diethyl phthalate, dibutyl phthalate or diisobutylphthalate, benzylbutyl phthalate, and di-(2-ethylhexyl) phthalate, respectively. We infrequently detected monoisononyl phthalate, mono-cyclohexyl phthalate, and mono-n-octyl phthalate, suggesting that human exposures to di-isononyl phthalate, dioctylphthalate, and dicyclohexyl phthalate, respectively, are lower than those listed above, or the pathways, routes of exposure, or pharmacokinetic factors such as absorption, distribution, metabolism, and elimination are different. Non-Hispanic blacks had significantly higher concentrations of MEP than did Mexican Americans and non-Hispanic whites. Compared with adolescents and adults, children had significantly higher levels of MBP, MBzP, and MEHP but had significantly lower concentrations of MEP. Females had significantly higher concentrations of MEP and MBzP than did males, but similar MEHP levels. Of particular interest, females of all ages had significantly higher concentrations of the reproductive toxicant MBP than did males of all ages; however, women of reproductive age (i.e., 20-39 years of age) had concentrations similar to adolescent girls and women 40 years of age. These population data on exposure to phthalates will serve an important role in public health by helping to set research priorities and by establishing a nationally representative baseline of exposure with which population levels can be compared.
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            Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease.

            High individuality causes laboratory reference ranges to be insensitive to changes in test results that are significant for the individual. We undertook a longitudinal study of variation in thyroid function tests in 16 healthy men with monthly sampling for 12 months using standard procedures. We measured serum T(4), T(3), free T(4) index, and TSH. All individuals had different variations of thyroid function tests (P < 0.001 for all variables) around individual mean values (set points) (P < 0.001 for all variables). The width of the individual 95% confidence intervals were approximately half that of the group for all variables. Accordingly, the index of individuality was low: T(4) = 0.58; T(3) = 0.54; free T(4) index = 0.59; TSH = 0.49. One test result described the individual set point with a precision of +/- 25% for T(4), T(3), free T(4) index, and +/- 50% for TSH. The differences required to be 95% confident of significant changes in repeated testing were (average, range): T(4) = 28, 11-62 nmol/liter; T(3) = 0.55, 0.3--0.9 nmol/liter; free T4 index = 33, 15-61 nmol/liter; TSH = 0.75, 0.2-1.6 mU/liter. Our data indicate that each individual had a unique thyroid function. The individual reference ranges for test results were narrow, compared with group reference ranges used to develop laboratory reference ranges. Accordingly, a test result within laboratory reference limits is not necessarily normal for an individual. Because serum TSH responds with logarithmically amplified variation to minor changes in serum T(4) and T(3), abnormal serum TSH may indicate that serum T(4) and T(3) are not normal for an individual. A condition with abnormal serum TSH but with serum T(4) and T(3) within laboratory reference ranges is labeled subclinical thyroid disease. Our data indicate that the distinction between subclinical and overt thyroid disease (abnormal serum TSH and abnormal T(4) and/or T(3)) is somewhat arbitrary. For the same degree of thyroid function abnormality, the diagnosis depends to a considerable extent on the position of the patient's normal set point for T(4) and T(3) within the laboratory reference range.
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              Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002).

              Describe thyrotropin (TSH) and thyroxine (T4) levels in the U.S. population and their association with selected participant characteristics. Secondary analysis of data from the National Health and Nutrition Examination Survey (NHANES) collected from 4392 participants, reflecting 222 million individuals, during 1999-2002. Hypothyroidism prevalence (TSH > 4.5 mIU/L) in the general population was 3.7%, and hyperthyroidism prevalence (TSH < 0.1 mIU/L) was 0.5%. Among women of reproductive age (12-49 years), hypothyroidism prevalence was 3.1%. Individuals aged 80 years and older had five times greater odds for hypothyroidism compared to 12- to 49-year-olds (adjusted odds ratio [OR] = 5.0, p = 0.0002). ORs were adjusted for sex, race, annual income, pregnancy status, and usage of thyroid-related medications (levothyroxine/thyroid, estrogen, androgen, lithium, and amiodarone). Compared to non-Hispanic whites, non-Hispanic blacks had a lower risk for hypothyroidism (OR = 0.46, p = 0.04) and a higher risk for hyperthyroidism (OR = 3.18, p = 0.0005), while Mexican Americans had the same risk as non-Hispanic whites for hypothyroidism, but a higher risk for hyperthyroidism (OR = 1.98, p = 0.04). Among those taking levothyroxine or desiccated thyroid, the adjusted risk for either hypothyroidism (OR = 4.0, p = 0.0001) or hyperthyroidism (OR = 11.4, p = 4 x 10(-9)) was elevated. Associations with known factors such as age, race, and sex were confirmed using this data set. Understanding the prevalence of abnormal thyroid tests among reproductive-aged women informs decisions about screening in this population. The finding that individuals on thyroid hormone replacement medication often remain hypothyroid or become hyperthyroid underscores the importance of monitoring.

                Author and article information

                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                November 2008
                10 July 2008
                : 116
                : 11
                : 1568-1575
                [1 ] Program on Reproductive Health and the Environment, Department of Obstetrics and Gynecology, University of California, San Francisco, San Francisco, California, USA
                [2 ] Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California, USA
                [3 ] Office of Policy, Economics and Innovation, U.S. Environmental Protection Agency, Washington, DC, USA
                [4 ] National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, USA
                [5 ] Department of Medicine, University of California, San Francisco, San Francisco, California, USA
                [6 ] National Resource Defense Council, San Francisco, California, USA
                [7 ] Pediatric Environmental Health Specialty Unit, University of California, San Francisco, California, USA
                [8 ] Wisconsin Division of Public Health, Madison, Wisconsin, USA
                [9 ] National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA
                [10 ] Institut National de l’Environnement Industriel et des Risques, Verneuil-en-Halatte, France
                [11 ] International Agency for Research on Cancer, Lyon, France
                [12 ] National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA
                [13 ] George Perkins Marsh Institute, Clark University, Worcester, Massachusetts, USA
                [14 ] School of Public Health, University of California, Berkeley, Berkeley, California
                [15 ] National Institute for Occupational Safety and Health, Atlanta, Georgia, USA
                [16 ] Environmental and Occupational Health Program, Maine Center for Disease Control and Prevention, Augusta, Maine, USA
                [17 ] Department of Biology, University of Massachusetts, Amherst, Amherst, Massachusetts, USA
                Author notes
                Address correspondence to T.J. Woodruff, University of California-San Francisco, Suite 1100, 1330 Broadway St., Oakland, CA 94612, USA. Telephone: (510) 986-8942; fax: (510) 986-8960. E-mail: woodrufft@ 123456obgyn.ucsf.edu

                The authors declare they have no competing financial interests.

                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.


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