Chemical warfare agents: estimating oral reference doses.

Health risk assessments for sites contaminated with chemical warfare agents require a comparison of the potential levels of exposure with a characterization of the toxic potency of each chemical. For noncancer health effects, toxic potency is expressed in terms of Reference Doses (RfD). A RfD is a daily exposure level or dose (usually expressed in units of milligrams of chemical per kilogram body weight per day) for the human population, including sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects. A daily exposure at or below the RfD is not likely to be associated with health risks, but as the amount of chemical that an individual is exposed to increases above the RfD, the probability that an adverse effect will occur also increases. A RfD is derived by first examining the available human or animal toxicity data to identify a dose or exposure that corresponds to a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL). The NOAEL is the exposure level at which there are no statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Effects may be produced at this level, but they are not considered to be adverse if they do not result in functional impairment or pathological lesions that affect the performance of the whole organism or which reduce an organism's ability to cope with additional challenge. The LOAEL is the lowest exposure level at which there are statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. If only a LOAEL is identified by the toxicity data, a NOAEL is estimated by dividing the LOAEL by a factor no greater than 10. This extrapolation factor of 10 or less is termed the LOAEL-to-NOAEL Uncertainty Factor (UFL). The NOAEL is also adjusted by the application of other Uncertainty Factors, including (1) a UFH < or = 10 to ensure that the resulting RfD protects segments of the human population that may be more sensitive to the chemical than the average person; (2) a UFA < or = 10 to extrapolate from the experimental animal species to humans; (3) a UFS < or = 10 to extrapolate from an experimental subchronic exposure study to a potential chronic exposure; and (4) a UFD < or = 10 to ensure that the resulting RfD is protective for all possible adverse effects, particularly those that may not have been adequately evaluated in the available studies. A Modifying Factor (MF), based on a qualitative professional assessment of the data, may also be used to account for other factors (e.g., deficiencies in the critical study) that are not adequately covered by the standard Uncertainty Factors. 1. Agent HD (Sulfur Mustard). RfDe = 7 x 10(-6) mg kg-1 d-1. A LOAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be "mild" in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level.

Medical students' evaluations of curriculum innovations at ten North American medical schools.

The authors recount medical educators' calls in the 1980s to reform general professional medical education by supplementing the standard lecture-lab biomedical curriculum with new biopsychosocial pedagogy and emphases. They then report selected medical students' evaluations of corresponding curriculum reform efforts that were in place by 1990 at eight U.S. and two Canadian medical schools known for being innovators. From interviews conducted in 1992-93 with a group of three to nine medical students at each school, the authors report two findings. First, the students' positive evaluations converged: at all ten schools they invariably appreciated curriculum reform efforts of any sort that encouraged individuation, connection, and diversity. Second, the students' negative evaluations diverged: specifically, those enrolled at the smaller schools with more distinctly teaching-service missions, schools where innovation was more wholesale, even extending across the entire curriculum, objected to curricula that provide too much in the way of new pedagogy and emphases and too little standard instruction; conversely, those enrolled at the larger schools with more comprehensive teaching-research-service missions, schools where innovation must be more piecemeal, often course by course, objected to curricula that provided too little in the way of new pedagogy and emphases and too much standard instruction. Suggesting that the smaller schools studied may be over-supplementing--and the larger schools under-supplementing--standard biomedical with new biopsychosocial pedagogy and emphases, the authors make two recommendations: first, that medical educators at schools of every size and sort contemplating curriculum reform of any scope recognize that medical students invariably appreciate educational opportunities for individuation, connection, and diversity; second, that the same educators, but especially those at the smaller teaching-service medical schools considering more wholesale innovation, recognize that medical students must soon compete for residencies and posts in a rapidly changing health care environment and thus want effective instruction per se, whether it be delivered by a lecturer or a tutor, in class or in tutorial, on a ward or in a clinic. That would be the meaning, they conclude, of student-centered learning, however it were tailored.

Comparison of water quality criteria and health advisories for 2,4,6-trinitrotoluene.

The U.S. Environmental Protection Agency (USEPA) has recently recommended health advisories (HAs) for 2,4,6-trinitrotoluene (TNT). The purpose of this brief article is to present these values so that the reader can compare them with the water quality criteria that have been proposed in another article (M. G. Ryon and R. H. Ross, 1990, Regul. Toxicol. Pharmacol. 11, 104-113). In that article, a water quality criterion of 140 micrograms/liter for TNT in drinking water was proposed, and in the present article the methodology by which USEPA calculated a lifetime HA of 2 micrograms/liter is presented. The reasons why the water quality criterion and the HA differ are discussed.

Water quality criteria for 2,4,6-trinitrotoluene.

The occurrence of the munitions compound 2,4,6-trinitrotoluene (TNT) in groundwater and surface water surrounding U.S. Army ammunition plants may result in contamination of local drinking water supplies. TNT exerts its primary toxic effect in humans on the hematologic system and liver, but it is also known to cause gastrointestinal effects and cataracts. Health effects data were analyzed for TNT and although no controlled human studies exist concerning the acute or chronic toxic effects of exposure to TNT, sufficient animal toxicity data are available to derive an ambient water quality criterion for the protection of human health. This paper summarizes the available literature on metabolism and toxicity of TNT in humans and animals. Based on noncarcinogenic mammalian toxicity data, and following the methodologies of the U.S. Environmental Protection Agency, an ambient water quality criterion for the protection of human health of 135 micrograms/liter is proposed when consumption of both contaminated water and fish is anticipated. For drinking water alone, the proposed criterion is 140 micrograms/liter.

Chemical scoring system for hazard and exposure identification.

To assist in the preliminary evaluation of compounds of toxicological and environmental interest to the U.S. Environmental Protection Agency (EPA), a scoring system was devised as a collaborative effort between the EPA and the Oak Ridge National Laboratory. The scoring system combines objective guidelines with professional judgment to evaluate chemicals and consists of 11 separate scoring parameters, 6 of which pertain directly to toxicity, e.g., aquatic toxicity and oncogenicity. The remaining parameters are related to environmental fate and occupational, consumer, and environmental exposure. The scoring system was designed to rapidly score chemicals in a minimal amount of time with readily available information. It is used by the Office of Toxic Substances of the EPA as a tool to help set priorities in conjunction with other criteria. It is particularly useful in performing preliminary evaluations involving large chemical classes, such as petroleum distillates.

Effects of prepartum protein restriction in the beef cow on immunoglobin content in blood and colostral whey and subsequent immunoglobin absorption by the neonatal calf.

Protein intake of first-calf beef heifers was restricted during the last 100 days of gestation, and the effects on passive transfer of colostral immunoglobins from the cow to the neonatal calf were examined. There were no significant correlations between concentration of immunoglobins (IgM, IgG1 and IgG2) in the sera or colostrum of the cow and prenatal crude protein consumption (.52 to .98 kg crude protein/day). Absorption of certain colostral immunoglobins (IgG1, and IgG2) by the calf were positively correlated (P less than .01) at 12, 18, 24 and 36 hr after birth to the maternal crude protein consumption. Colostrum was collected from the first milkings of pluriparous dairy cows, and then freeze-dried, mixed and reconstituted to be equivalent to 1 liter of colostrum. Mean IgG1 concentrations for the high and low protein groups were 6.02 +/- .90 and .78 +/- .15 mg . ml-1 (P less than .01), respectively. No relationship (P greater than .05) was found between the concentration of IgM in calf sera and daily crude protein intake of the dam. These data indicate that there was a selective decrease in absorption of IgG1 and IgG2 in calves from heifers fed low protein prenatal diets.

Estrogen in plasma of parturient paretic and normal cows.

The endocrine factors associated with parturient paresis have not been defined totally. Estrogens stimulate uptake of calcium by bone. Since secretion of estrogen increases dramatically as parturition approaches, estrogen may be involved in homeostatic mechanisms regulating calcium metabolism. Plasma was collected for 30 days (-30) prepartum to 5 days (+5) postpartum from six Holstein and nine Jersey cows approaching three or more lactations. Of all cows, six Jerseys contracted parturient paresis. Estradiol and estrone were analyzed by radioimmunoassay, total calcium and total magnesium by atomic absorption spectrophotometry, and total phosphorus by colorimetry. Data were grouped into periods respresenting days -30 to -21, -20 to -11, -10 to -6, -5 to -4, -3 to -2, -1, 0 (parturition), +1, +2 to +3, and +4 to +5. Calcium in plasma was lower in parturient paresis cows on days +1 and +2 to +3, and magnesium was higher during the same periods but lower on days -4 to -5. Total phosphorus, estrone, and estradiol of normal cows and those with parturient paresis were not different. During the entire sampling period, phosphorus and estradiol were similar in both groups while magnesium was higher and calcium lower in cows with parturient paresis. Estrone was lower in cows with parturient paresis. Lower estrone in cows with parturient paresis may be predisposing for parturient paresis.

Growth rate and secretion of pituitary hormones in relation to age and chronic treatment with thyrotropin-releasing hormone in prepubertal dairy heifers.

Holstein heifers were treated with synthetic thyrotropin-releasing hormone (TRH) or saline twice daily from one week through 6 mo of age. Plasma concentrations of prolactin (PRL) and thyrotropin (TSH) were elevated (P less than .01) within 30 min after the first TRH injection (1 week of age). At 1 and 3 mo of treatment, PRL and TSH increased in response to TRH, although the TSH response was reduced (P less than .01) as compared to the first day of treatment. Although plasma growth hormone (GH) appeared to be elevated following the first TRH injection, this effect was not statistically significant (P less than .05), nor was it significantly influenced by treatment following subsequent TRH injections. None of the 3 hormones, PRL, TSH or GH, was elevated following the final TRH injection at 6 mo of age. In contrast, plasma concentrations of PRL and TSH were increased in a control heifer injected with TRH at 6 mo. These data indicate that hormonal responsiveness to TRH stimulation decreases with continued twice daily treatment at doses of TRH used in the present studies. Examination of weight gains indicated that chronic treatment with TRH was associated with increased growth rate through 6 mo of age (10.6% increased average daily gains P less than .10), which was exhibited in a steeper slope (P less than .05) of the growth curve in the TRH group. Feed intake was slightly greater in TRH heifers, although feed efficiency (kg feed/kg gain) was not different between the two groups. Plasma concentrations of PRL increased (P less than .01) with age (r = +0.938) in control heifers while plasma TSH and GH were not significantly related to age. This observation establishes a positive correlative relationship between PRL secretion and the approach of puberty in the dairly heirfer. It was also noted that elevation of PRL secretion by TRH treatment was associated with significant advancement of age at first observed estrus (9.4 vs. - 10.5 mo) suggesting that a functional relationship between PRL secretion and puberty may exist in dairy heifers.