Addressing human variability in risk assessment--the robustness of the intraspecies uncertainty factor.

Addressing human variability and sensitive subpopulations is one of the challenges of risk assessment and is an important aspect of the Food Quality Protection Act, the law passed in 1996 that regulates food use pesticides in the United States. The intraspecies uncertainty factor is intended to address differences in susceptibility within the human population. This paper examines the history and scientific basis for the intraspecies uncertainty factor. Our best source of knowledge about human variability in the response to chemicals comes from clinical trials of pharmaceuticals. This large body of data allows both qualitative and quantitative characterization of variability in pharmacokinetic and pharmacodynamic parameters in the general population and in subgroups such as children. The preponderance of evidence in the areas of pharmacodynamics and pharmacokinetics supports the routine use of an intraspecies uncertainty factor in the range of 1-10 as being protective of greater than 99% of the human population. The intraspecies uncertainty factor is highly protective of various subpopulations, including infants and children.

Human bladder cancer: evidence for a potential irritation-induced mechanism.

Bladder cancer is one of the most common human cancers, constituting about 6% and 2% of all cancers among males and females, respectively. Over 90% of all bladder cancers are transitional cell carcinomas, with most of the remainder being squamous cell carcinomas. Smoking and occupational exposure to aromatic amines and other agents are most prominent among the risk factors identified. Inflammation of the bladder, largely by infection but also by stones or a combination of the two, may play some role in human bladder cancer development. The association between inflammation and cancer appears to be stronger for squamous cell than for transitional cell carcinoma. Stones and infection can be important factors in the development of bladder tumours in rodents, but the tumours are predominantly transitional cell rather than squamous cell carcinomas.

International safety assessment of pesticides: dithiocarbamate pesticides, ETU, and PTU--a review and update.

For the last 30 years the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) has carried out toxicological evaluations and safety assessments of dithiocarbamate pesticides, continuously adjusting previous appraisals in the light of new data and advances in the understanding of the principles and mechanisms of toxic action of these compounds. The historical narrative of the evaluative process is followed by an account of the present international safety assessment status of the dithiocarbamate pesticides so far examined by the JMPR. They are ferbam, mancozeb, maneb, metiram, nabam, propineb, thiram, zineb, ziram, and the associated substances, ethylenethiourea (ETU) and propylenethiourea (PTU).

Cocaine-mediated disruption of microfilament integrity within neural-fold neuroepithelial cells of chick embryos cultured in vitro.

The effects of cocaine on microfilaments within neuroepithelial cells of neurula-stage chick embryos cultured in vitro were investigated by an actin indirect immunofluorescence procedure. Results of this study suggest that the cocaine-induced inhibition of neural-fold closure in chick embryos cultured in vitro reported previously is mediated by a loss of microfilament integrity within the neuroepithelium.

Investigation of the developmental toxicity of cocaine in in vitro cultured chick embryos: Correlation of effects with intra-embryonic drug levels.

The effects of cocaine and its primary metabolites, benzoylecgonine and ecgonine, on early embryogenesis were investigated in in vitro cultured chick embryos, and levels of cocaine and benzoylecgonine were measured in the embryo and in the culture medium. Neurulation was the only developmental process shown to be sensitive to cocaine. Closure of neural folds was inhibited within 4 hr of treatment of stage 6-8(-) embryos with 170-340 mug cocaine hydrochloride in 1 ml culture medium. Cocaine levels within embryos treated with 340 mug cocaine hydrochloride decreased from approximately 11 to 5 mug/embryo between 20 min and 4 hr of culture. Cocaine effects were more pronounced in continuously treated embryos.

Goitrogens and thyroid follicular cell neoplasia: evidence for a threshold process.

Thyroid neoplasia can result from many different causes. These include low iodine diets, subtotal thyroidectomy, radioactive iodine, natural goitrogens such as rape seed and cabbage, chemotherapeutic agents such as sulfathiazole, and pesticides such as amitrole. All of these appear to act through either direct or indirect interference with thyroid hormone synthesis. Decreased circulating levels of thyroid hormones in the blood result in increased release of thyroid-stimulating hormone by the anterior pituitary gland. This, in turn, results in hypertrophy and hyperplasia of the thyroid without a corresponding increase in blood thyroid hormone levels. Hyperplasia of the pituitary is also observed due to increased functional demand for continued production of thyroid-stimulating hormone. After prolonged stimulation of the pituitary/thyroid axis, hyperplasia may progress to neoplasia. Cessation of exposure prior to the induction of neoplasia results in a return to the normal state. It is clear that some degree of thyroid inhibition can be accommodated within the bounds of the normal feedback mechanism without the induction of either hyperplasia or neoplasia. A threshold for thyroid follicular neoplasia is therefore indicated.