The human relevant potency threshold: reducing uncertainty by human calibration of cumulative risk assessments.

The 2008 National Research Council report "Phthalates and Cumulative Risk Assessment: Tasks Ahead," rejected the underlying premises of TEQ-like approaches - e.g., chemicals are true congeners; are metabolized and detoxified similarly; produce the same biological effects by the same mode of action; exhibit parallel dose response curves - instead asserting that cumulative risk assessment should apply dose addition (DA) to all chemicals that produce "common adverse outcomes" (CAOS). Published mixtures data and a human health risk assessment for phthalates and anti-androgens were evaluated to determine how firmly the DA-CAOS concept is supported and with what level of statistical certainty the results may be extrapolated to lower doses in humans. Underlying assumptions of the DA-CAOS concept were tested for accuracy and consistency against data for two human pharmaceuticals and its logical predictions were compared to human clinical and epidemiological experience. Those analyses revealed that DA-CAOS is scientifically untenable. Therefore, an alternative approach was developed - the Human-Relevant Potency-Threshold (HRPT) - that appears to fit the data better and avoids the contradictions inherent in the DA-CAOS concept. The proposed approach recommends application of independent action for phthalates and other chemicals with potential anti-androgenic properties at current human exposure levels.

Maternal age as a risk factor for hypospadias.

PURPOSE: Hypospadias incidence rates have been widely reported to be increasing. During the last 20 years there has been a significant increase in the number of women who delay childbearing until their mid 30s. Therefore, it was of interest to determine if increasing maternal age is an independent risk factor for hypospadias. MATERIALS AND METHODS: Data from the New York State Department of Health and California Birth Defects Monitoring Program were analyzed from 1983 to 1996 by maternal age groups of less than 20, 20 to 24, 25 to 29, 30 to 34, and 35 or greater years. A Poisson model was fitted to the data from each state using maternal age and year of birth from which relative rates were calculated. RESULTS: Our analysis revealed that advancing maternal age is significantly associated with hypospadias and is most evident for severe cases. For example, in California a 50% increase in severe cases was demonstrated for children of mothers older than 35 years compared to mothers younger than 20 years (p <0.05). CONCLUSIONS: Hypospadias is significantly associated with increasing maternal age. Women who elect to delay childbearing until their mid 30s or later should be aware that their offspring are at increased risk of hypospadias.

An examination of the sensitivity of reported trends in childhood leukemia incidence rates to geographic location and diagnostic coding (United States).

BACKGROUND: There have been conflicting reports of increased incidence of childhood leukemia in the United States with some, but not other, registries reporting increasing rates over the past two decades. Because of the reported discrepancy in childhood leukemia incidence rates an analysis of the SEER database was undertaken. METHODS: The latest SEER data (1973-1995) were analyzed for trends in childhood (age 0-14) leukemia incidence rates by histologic group (all leukemia combined, acute lymphocytic leukemia (ALL), acute mylogenous leukemia (AML), and other acute leukemia) for each SEER reporting region. RESULTS: A significant increase in ALL during 1973-1995 was observed in the combined SEER data, but the increase was a function of whether the first 3 years, data from the SEER Detroit reporting region are included. For the years 1973-1975 the Detroit region reported to much lower rates for ALL and much higher rates for "other acute leukemias" relative to the other SEER regions, resulting in an exaggerated temporal increase in ALL. CONCLUSION: Excluding both the temporal variability, and coding differences for Detroit in the 1973-1975 time frame, there has been no significant increase in childhood leukemia of any histologic group or age category in the United States from the 1970s to 1990s.

Environmental endocrine modulators and human health: an assessment of the biological evidence.

Recently, a great deal of attention and interest has been directed toward the hypothesis that exposure, particularly in utero exposure, to certain environmental chemicals might be capable of causing a spectrum of adverse effects as a result of endocrine modulation. In particular, the hypothesis has focused on the idea that certain organochlorine and other compounds acting as weak estrogens have the capability, either alone or in combination, to produce a variety of adverse effects, including breast, testicular and prostate cancer, adverse effects on male reproductive tract, endometriosis, fertility problems, alterations of sexual behavior, learning disability or delay, and adverse effects on immune and thyroid function. While hormones are potent modulators of biochemical and physiological function, the implication that exposure to environmental hormones (e.g., xenoestrogens) has this capability is uncertain. While it is reasonable to hypothesize that exposure to estrogen-like compounds, whatever their source, could adversely affect human health, biological plausibility alone is an insufficient basis for concluding that environmental endocrine modulators have adversely affected humans. Diethylstilbestrol (DES) is a potent, synthetic estrogen administered under a variety of dosing protocols to millions of women in the belief (now known to be mistaken) that it would prevent miscarriage. As a result of this use, substantial in utero exposure to large numbers of male and female offspring occurred. Numerous studies have been conducted on the health consequences of in utero DES exposure among the adult offspring of these women. There are also extensive animal data on the effects of DES and there is a high degree of concordance between effects observed in animals and humans. The extensive human data in DES-exposed cohorts provide a useful basis for assessing the biological plausibility that potential adverse effects might occur following in utero exposure to compounds identified as environmental estrogens. The effects observed in both animals and humans following in utero exposure to sufficient doses of DES are consistent with basic principles of dose response as well as the possibility of maternal dose levels below which potential non-cancer effects may not occur. Significant differences in estrogenic potency between DES and chemicals identified to date as environmental estrogens, as well as an even larger number of naturally occurring dietary phytoestrogens, must be taken into account when inferring potential effects from in utero exposure to any of these substances. The antiestrogenic properties of many of these same exogenous compounds might also diminish net estrogenic effects. Based on the extensive data on DES-exposed cohorts, it appears unlikely that in utero exposure to usual levels of environmental estrogenic substances, from whatever source, would be sufficient to produce many of the effects (i.e., endometriosis, adverse effects on the male reproductive tract, male and female fertility problems, alterations of sexual behavior, learning problems, immune system effects or thyroid effects) hypothesized as potentially resulting from exposure to chemicals identified to date as environmental estrogens.

Chloroform mode of action: implications for cancer risk assessment.

Risk assessment methodology, particularly pertaining to potential human carcinogenic risks from exposures to environmental chemicals, is undergoing intense scrutiny from scientists, regulators, and legislators. The current practice of estimating human cancer risk is based almost exclusively on extrapolating the results of chronic, high-dose studies in rodents to estimate potential risk in humans. However, many scientists are questioning whether the logic used in this current risk assessment methodology is the best way to safeguard public health. A major tool of human cancer risk assessment is the linearized multistage (LMS) model. The LMS model has been identified as an aspect of risk assessment that could be improved. One way to facilitate this improvement is by developing a way to incorporate a carefully derived, more biologically relevant mechanism of action data on carcinogenesis. Recent data on chloroform indicate that the dose-response relationship for chloroform-induced tumors in rats and mice is nonlinear, based upon events secondary to cell necrosis and subsequent regeneration as the likely mode of action for the carcinogenic effects of chloroform. In light of these data, there is a sound scientific basis for removing some of the uncertainty that accompanies current cancer risk assessments of chloroform. The following points summarize the critical data: (1) a substantial body of data demonstrates a lack of direct in vivo or in vitro genotoxicity of chloroform; (2) chloroform induces liver and kidney tumors in long-term rodent cancer bioassays only at doses that induce frank toxicity at these target sites; (3) the chloroform doses required to produce tumors in susceptible species exceed the MTD, often by a considerable margin; (4) cytotoxicity and compensatory cell proliferation are associated with the chloroform doses required to induce liver or kidney tumors in susceptible rodent species; (5) there are no instances of chloroform-induced tumors that are not preceded by this pattern of dose-dependent toxic responses; (6) it is biologically plausible that cytolethality leads to chronically stimulated cell proliferation and related events such as inflammation and growth stimulation which act to initiate and promote the carcinogenic process; and (7) the consistently linked cellular events of cytolethality and subsequent cell proliferation, for which doses of no adverse effect have been clearly shown to exist, are one of the biological prerequisites for chloroform-induced tumors in animals. Based on these data, it is inappropriate to extrapolate cancer risk from high doses that produce necrosis and regenerative cell proliferation to low doses that do not with a model that presumes genotoxicity and a linear dose-response relationship. The weight of the scientific evidence concerning chloroform-induced tumors in rodents is consistent with and supports a cancer risk assessment methodology based on mode of action as the basis for establishing regulatory standards for this compound.