Development of toxicity values and exposure estimates for tetrabromobisphenol A: application in a margin of exposure assessment.

Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2-year bioassay for TBBPA. The objective of the present study was to develop a cancer-based and a non-cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2-year and 13-week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg(-1) day(-1) based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg(-1) day(-1) based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E(-7) to 3.9 E(-6) mg kg(-1) day(-1) based on age-adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E (-7) to 8.4 E(-5) mg kg(-1) day(-1). Resulting margin of exposure (MOE) values were > 800 000 for non-cancer endpoints and > 32,000,000 for cancer-based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA.

Antibiotic use and risk of gynecological cancer.

OBJECTIVES: Several studies addressed the association between antibiotic use and breast cancer risk. The objective of this study was to assess the association between antibiotic use and risk of cervical, ovarian, and uterine cancer. STUDY DESIGN: We carried out a population-based case-control study using data from Saskatchewan Health administrative databases (Canada) between the years 1981 and 2000. Cases were matched to 4 controls, using incidence density sampling. The effect of dosage and timing of antibiotic use, over a minimum of 15 years before diagnosis, on cervical, ovarian, or uterine cancer risk was assessed. Number of prescriptions and number of pills were used as exposure definitions. The effect of different classes of antibiotics on cancer risk was also studied. RESULTS: A total of 1225 cancer cases [192 cervical, 445 ovarian, and 588 uterine] and 4900 matched controls were included in this study. Antibiotic exposure (number of prescriptions) during the period of 1-15 years in the past was significantly associated with a reduced risk of cervical cancer; Relative Risk (RR)=0.40, 0.31, 0.26, and 0.29 for the four exposure quartiles, respectively. No association was found for ovarian or uterine cancer. When number of pills was considered, similar results were found. There was no effect of the timing or class of antibiotic exposure on cervical cancer risk. CONCLUSIONS: Antibiotic exposure up to 15 years in the past was associated with a decreased risk of cervical cancer. The lack of temporal trends and the absence of class specific effects suggest a non-causal relationship.

Hormonal breast cancer agents: implications for the primary care provider.

PURPOSE: Over 2 million breast cancer survivors are in the United States, making women with breast cancer the largest group of cancer survivors. The purpose of this article is to review the current knowledge regarding survivorship issues in women with early-stage, estrogen receptor-positive breast cancer, focusing on advances in hormonal therapies for reducing risk of recurrence. DATA SOURCES: Published research studies, clinical treatment guidelines, and ongoing clinical trials. CONCLUSIONS: Innovations in antiestrogenic and estrogen modulator therapies are an important aspect of ongoing care after primary breast cancer treatment. Primary care providers may play an important role in monitoring potential complications of antiestrogenic treatment. IMPLICATIONS FOR PRACTICE: This article reviews the current state of the science in hormonal breast cancer agents for breast cancer survivors. With the high incidence and prevalence of breast cancer, primary care providers need to be aware of the potential short- and long-term health risks and benefits of hormonal therapies for breast cancer survivors.

The role of personal health concerns and knowledge of the health effects of hormone replacement therapy (HRT) on the ever use of HRT by menopausal women, aged 50-54 years.

UNLABELLED: Previous studies of factors important in a woman's decision to use hormone replacement therapy (HRT) infrequently have simultaneously considered the effects of personal concern for chronic medical disorders that begin at the time of the menopause (such as osteoporosis and heart disease) and knowledge of the beneficial and adverse effects of HRT on these conditions (increased risk of uterine and breast cancers). Moreover, few studies have been performed in broad-based populations that have included black women. This study was undertaken to determine the cross-sectional association of concern for chronic medical disorders that begin at the time of the menopause and knowledge of the effects of HRT on these disorders on the ever use of HRT in a biracial cohort of postmenopausal women. Two hundred eight-eight women, aged 50-54 years, who were members of an HMO, who reported their last menstrual period to be more than 1 year ago, and who were aware of HRT, were examined by questionnaire. Of the cohort, 21.2% were black. Concern for chronic medical disorders that begin at the time of the menopause was modest (approximately 50%). Knowledge of the effects of HRT on breast cancer, uterine cancer, and heart disease was low (approximately 30%). Only for osteoporosis was knowledge high (approximately 65%). On adjusted analysis, concern for heart disease was weakly associated with ever use of HRT, but only for white women. The factors most strongly associated with initiating HRT were a doctor's recommendation to use HRT and satisfaction with a doctor's counseling. Having menopausal symptoms was associated with ever use of HRT in black women. Black women were only 30% as likely as white women to ever use HRT after adjustment for baseline differences. CONCLUSION: In this study, personal concerns for medical conditions that begin at the time of the menopause and knowledge of the effects of HRT on these conditions were low. Only personal concern for heart disease among white women was independently, but weakly, associated with ever use of HRT. Black women were less likely than white women to ever use HRT, even after adjustment for baseline differences between them.

Capturing and clustering women's judgment policies: the case of hormonal therapy for menopause.

Two hundred sixty-five women estimated the likelihood that they would take estrogen plus progestin to alleviate menopausal symptoms when faced with hypothetical cases varying in degree of hot flashes and risk of osteoporosis and cancer. Clustering of their judgment policies revealed four groups of women with respect to their approach to this decision. These groups of women were significantly different from each other on educational level, perceived experience of stress, and attitudes toward menopause and use of medications. Willingness to take hormonal therapy across all cases was related to attitudes about, and knowledge of, menstruation, perceived stress, mother's experience with menstrual problems, severity of symptoms, and use of vitamins. While there have been previous attempts to cluster rater policies, the current study represents a novel attempt to understand the differences between people who appear to have different policies about a decision problem, in this case, whether or not to take hormone therapy to counter menopausal symptoms.

The use of combined estrogen-progestin replacement therapy.

The evaluation of innovations which use old technology poses different problems than does the evaluation of new technologies. The main necessity is the targeting of its use rather than the technology itself. The need to evaluate the extent of use and its problems is illustrated by the example of progestin use among menopausal and postmenopausal women in the United States. There progestins are not officially approved for use in menopause, even though they have been on the market for a long time with other indications. Estrogen-replacement therapy was widely used from the early 1960s until 1975, when the claim that estrogens cause endometrial cancer notably decreased their use. The use of estrogens increased again in the early 1980s, and one reason for this revival was the claim that progestins offered protection against endometrial cancer. When recommendations for combined estrogen-progestin therapy have been made, other health effects have been ignored. Two consensus conferences as well as the drug control authority have recommended against combined estrogen-progestin therapy until further research is completed. Absence of good research, specialization in medicine, and advantages for prescribers and the drug industry may have contributed to the wide use of this unassessed treatment. Possible solutions for prevention of the diffusion of these kinds of innovations are discussed.

Compliance with hormone therapy.

The analysis of compliance with hormonal replacement therapy in postmenopausal women must take into account the physician's knowledge of and willingness to prescribe such treatment and the patient's acceptance of the risks and benefits. Studies have shown that most women receiving oral therapy take their medication only sporadically, and those who discontinue treatment usually do so because of the fear of endometrial cancer. Both physicians and patients should be made aware that the addition of progestogen can greatly lessen this risk. Estrogen therapy has been shown to offer significant benefits, notably a reduction in the incidence of osteoporosis-related fractures. Epidemiologic models can be useful in showing both physicians and patients that hormonal treatment is safe and effective. Noncompliance, stemming from side effects or the problem of forgetting to take medications, can be improved through the use of the transdermal estrogen formulation. This product has been associated with excellent tolerability; local and systemic adverse reactions have been minimal, and any problems with unscheduled bleeding or hyperplasia can be circumvented through the addition of progestogens.

[Comparative quantitative assessment of a carcinogenic effect taking intercurrent mortality into account]. / Sravnitel'naia kolichestvennaia otsenka kantserogennogo éffekta s uchetom interkurrentnoi smertnosti.

The paper discusses the advantages offered by the statistical evaluation of experimental carcinogenic effect with due regard to mortality from concomitant pathology. The method used complex tables of contingents and analysis was carried out separately in 3 groups of tumors--independent of mortality, fatal and incidental ones. The method was compared with standard procedures which do not take care of the said mortality rate (table of contingents 2 X 2 and precise procedure of Fisher). The data on development of 1,2-dimethylhydrazine-induced tumors of the skin, uterus and ovaries in 5 strains of mice were used in the study.

Genotoxicity and carcinogenicity of fluorocarbons: assessment by short-term in vitro tests and chronic exposure in rats.

Two short-term in vitro tests for mutagenicity (Salmonella reverse mutation and BHK21 cell transformation) were conducted on a series of fluorocarbons. Some of these materials (FC22, FC31, FC142b, FC143, and FC143a) were found to be positive in one or both of the tests and could therefore be considered as being potentially carcinogenic to animals. Such activity was not anticipated for what were previously considered inert materials and in consequence several examples of these fluorocarbons, which represented different combinations of short-term test results, were tested for carcinogenicity in limited in vivo bioassays. In these studies, rats were dosed for 1 year by gavage 5 days a week with either FC22, FC31, FC133a, FC134a, or FC143a dissolved in a corn-oil at a single dosage of 300 mg/kg body weight. The animals were then observed until week 125 with detailed necropsy at termination. The study revealed that FC31 was a potent carcinogen (to the rat stomach), a result which reflected the short-term test predictions, but FC133a, which gave a negative response in both the in vitro assays, induced a high incidence of reproductive tract tumors. The weak bacterial mutagens FC22 and FC143a did not induce tumors in this study, and the nonmutagenic FC134a was without overt carcinogenic activity. It is concluded that, while recognizing the limitations of the in vivo component of this study, the short-term tests were only partially successful in identifying potential carcinogens for this series of chemicals. Fluorocarbon 31 was a potent carcinogen which was first identified by bacterial mutation and cell transformation, whereas the equally potent carcinogen FC133a was not so identified. The lack of genotoxic activity with this particular compound leads us to believe that the carcinogenic activity may be due to mechanisms other than those which involve direct DNA interactions.

Exogenous estrogens and endometrial cancer: a case-control study and assessment of potential biases.

Eighty-eight cases with newly diagnosed carcinoma of the endometrium and 177 age-matched neighborhood controls were interviewed to test the hypothesis that exogenous estrogens lead to an increased risk of endometrial cancer. Forth-five per cent of the cases and 22% of the controls reported a history of estrogen use which yielded an odds ratio of 2.9 (confidence interval (Cl) 1.7-5.1). Women with five or more years of estrogen use had an odds ratio of 8.6 (Cl 3.2-23.0). Approximately 80% of the estrogen users had used conjugated equine estrogens. For these women the odds ratio was 4.0 (Cl 1.9-8.4) for daily dosages of more than 1 mg of estrogen. Several sources of bias which might affect the estrogen association were investigated. These included comparability of cases and controls, selection procedures, difference between estrogen users and nonusers, exclusion of controls who had hysterectomy, source of estrogen information, and differential recall. The concept or medical surveillance was evaluated by access to medical care and prior history of dilatation and curettage. The strong association between exogenous estrogen use and endometrial cancer remained after consideration for the effects of these biases.

Estrogen use in postmenopausal women--costs, risks, and benefits.

The cost effectiveness of estrogen use in postmenopausal women was analyzed with use of data from the medical and epidemiologic literature. Risks of endometrial cancer, uterine bleeding, and gallbladder disease were weighed against benefits associated with relief of menopausal symptoms and with prevention of osteoporosis and consequent fractures. Net effects on life expectancy are probably small in either direction, although they are likely to be positive in women with existing osteoporosis or prior hysterectomy. Treatment appears to be relatively cost effective in menopausal women with prior hysterectomy or osteoporosis but does not appear to be cost effective as a prophylactiv measure in asymptomatic women with intact uteri. For women with menopausal symptoms and intact uteri, the decision to prescribe estrogens for the individual patient and the cost effectiveness of estrogen use at the societal level depend critically on the subjective values assigned to symptomatic relief.

The place of oestriol therapy after menopause.

The therapeutic principles covering sex hormone replacement therapy after menopause have undergone profound modification in recent years. Initial optimism regarding benefits, proven and unproven, was followed by deep pessimism because of potential serious adverse effects. Some degree of equilibrium has resulted from the application of risk-benefit and cost-effectiveness formulae to such hormone replacement regimens. Cost-effectiveness analysis in particular has highlighted the fact that different hormones or hormone combinations can markedly affect the therapeutic outcome. The purpose of the present paper is to examine the place of oestriol therapy after menopause based on such risk-benefit analyses. Oestriol, it would appear, has the potential for reduced risk but similar benefit to alternative oestrogen or oestrogen-progestogen combinations. The potential risks and benefits of long-term oestrogen therapy are therefore surveyed from the general standpoint of all oestrogens and the specific role of oestriol alone.