Risk Assessment for Developmental Toxicity: Airborne Occupational Exposure to Ethanol and Iodine

Dean Mattison explains hazard identification, hazard characterization and exposure characterization as furnishing a foundation for Risk assessment generally. He then illustrates their application in assessing the fetal Risk posed by two common substances. Ultimately, he argues that only after Risks have been so examined can women of child bearing age (or anyone) decide what if any measures are appropriate to avoid them

Clinical Therapeutics in Pregnancy

Most drugs are not tested for use during pregnancy, consequently, labeling, which may include information about fetal safety, includes nothing about dosing, efficacy, or maternal safety. Yet these are concerns of health care providers considering treatment of disease during pregnancy. Therefore, the practitioner treats the pregnant woman with the same dose recommended for use in adults (typically men) or may decide not to treat the disease at all. However, is the choice of not treating a woman during pregnancy better than dealing with the challenges which accompany treatment? This paper, which summarizes metabolic and physiologic changes induced by pregnancy, illustrates that standard adult dosing is likely to be incorrect during pregnancy

Propylthiouracil (PTU) Hepatoxicity in Children and Recommendations for Discontinuation of Use

Propylthiouracil (PTU) was introduced for clinical use in July 1947 for Graves' disease (GD) treatment. Over the 60 years that this medication has been used, reports of PTU-related liver failure and death have accumulated. On October 28, 2008, an expert panel evaluated PTU drug safety in children at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) It is estimated that about 4000 pediatric patients per year with GD are being treated with antithyroid drugs (ATDs) in the United States, and up to 30% of pediatric patients with GD are being treated with PTU. The risk of severe PTU-induced liver failure is estimated as 1 in 2000–4000 children. The number of children developing reversible PTU-induced liver injury is estimated to be at least 1 in 200. Routine biochemical surveillance of liver function and hepatocellular integrity is not useful in identifying children who will develop liver failure. Children appear to be at higher risk for PTU-induced liver injury than adults. PTU should not be used as first line therapy for the treatment of GD in children. Current PTU use in children taking this medication should be stopped in favor of alternate therapies

Sex Differences in Drug Disposition

Physiological, hormonal, and genetic differences between males and females affect the prevalence, incidence, and severity of diseases and responses to therapy. Understanding these differences is important for designing safe and effective treatments. This paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women

Severity scoring of manganese health effects for categorical regression

Characterizing the U-shaped exposure response relationship for manganese (Mn) is necessary for estimating the risk of adverse health from Mn toxicity due to excess or deficiency. Categorical regression has emerged as a powerful tool for exposure-response analysis because of its ability to synthesize relevant information across multiple studies and species into a single integrated analysis of all relevant data. This paper documents the development of a database on Mn toxicity designed to support the application of categorical regression techniques. Specifically, we describe (i) the conduct of a systematic search of the literature on Mn toxicity to gather data appropriate for dose-response assessment; (ii) the establishment of inclusion/exclusion criteria for data to be included in the categorical regression modeling database; (iii) the development of a categorical severity scoring matrix for Mn health effects to permit the inclusion of diverse health outcomes in a single categorical regression analysis using the severity score as the outcome variable; and (iv) the convening of an international expert panel to both review the severity scoring matrix and assign severity scores to health outcomes observed in studies (including case reports, epidemiological investigations, and in vivo experimental studies) selected for inclusion in the categorical regression database. Exposure information including route, concentration, duration, health endpoint(s), and characteristics of the exposed population was abstracted from included studies and stored in a computerized manganese database (MnDB), providing a comprehensive repository of exposure-response information with the ability to support categorical regression modeling of oral exposure data

Using Systematic Reviews and Meta-Analyses to Support Regulatory Decision Making for Neurotoxicants: Lessons Learned from a Case Study of PCBs

We examined prospective cohort studies evaluating the relation between prenatal and neonatal exposure to polychlorinated biphenyls (PCBs) and neurodevelopment in children to assess the feasibility of conducting a meta-analysis to support decision making. We described studies in terms of exposure and end point categorization, statistical analysis, and reporting of results. We used this evaluation to assess the feasibility of grouping studies into reasonably uniform categories. The most consistently used tests included Brazelton's Neonatal Behavioral Assessment Scale, the neurologic optimality score in the neonatal period, the Bayley Scales of Infant Development at 5-8months of age, and the McCarthy Scales of Children's Abilities in 5-year-olds. Despite administering the same tests at similar ages, the studies were too dissimilar to allow a meaningful quantitative examination of outcomes across cohorts. These analyses indicate that our ability to conduct weight-of-evidence assessments of the epidemiologic literature on neurotoxicants may be limited, even in the presence of multiple studies, if the available study methods, data analysis, and reporting lack comparability