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Biomedical subjects

E V Sargent

Publications and source records attributed to E V Sargent.

16 recordsLinked to original sources
PubMed1999

Occupational hazard evaluation of p-bromobenzyl bromide from tests for genotoxicity.

As part of an occupational hazard evaluation, p-bromobenzyl bromide (p-BBB) was evaluated for genotoxic activity in the Ames microbial mutagenicity assay, the alkaline elution assay for DNA strand breaks in rat hepatocytes and the in vitro chromosome aberration assay in Chinese hamster ovary cells. The compound produced equivocal results in the microbial mutagenicity assay but was negative in the alkaline elution assay for DNA strand breaks in rat hepatocytes. The compound produced weakly positive results in the in vitro chromosome aberration assay. There was substantial cytotoxicity in all three assays. It is concluded that p-BBB is weakly genotoxic.

Animals↗
PubMed1996

Performance-based exposure control limits for pharmaceutical active ingredients.

For many years pharmaceutical companies have established employee exposure limits for the active ingredients used in their products. Historically these limits were derived using traditional risk assessment methods. Because the trend in the pharmaceutical industry is to identify and develop more selective drugs of increasing potency, and because of the difficulty in identifying no-effect levels for certain drugs, a new performance-based approach for setting limits was developed. This method involves assigning materials into one of five hazard categories according to their inherent toxicological and pharmacological properties. The criteria used to assign compounds into performance-based exposure control limit (PB-ECL) categories focus on the degree to which exposure impacts human health. These assignments dictate the level of containment required to assure employee safety that is achieved through the use of engineering controls and safe handling practices. Several matrices were developed to specify general design concepts and controls for unit operations in laboratory and manufacturing operations. Containment options range from conventional handling practices for low potency (PB-ECL Category 1) materials, to technologically advanced systems that result in essentially no open handling for potent or toxic (PB-ECL Category 3) materials, to state-of-the-art facilities employing closed processes and use of robotics for extremely potent (PB-ECL Category 5) materials.

Containment of Biohazards↗
PubMed1995

A collaborative evaluation of seven alternatives to the Draize eye irritation test using pharmaceutical intermediates.

Much of the data which have been generated on in vitro alternatives to the Draize eye irritation test have dealt with compounds within a specific chemical class or product category. However, in the pharmaceutical industry, it is often necessary to evaluate materials which are not related in structure or properties. It was thus decided to evaluate a diverse series of chemicals in seven in vitro methods for estimating ocular irritation. Thirty-seven test materials were chosen to represent a broad range of pH, solubility, and in vivo irritation potential. Assays were chosen to include as many different types of end points as practical. The group of assays was composed of TOPKAT (assessing structure-activity relationships), bovine corneal opacity-permeability (BCO-P; corneal opacity/toxicity), Eytex (protein coagulation), neutral red uptake (cytotoxicity), MTT in living dermal equivalent (cytotoxicity), Microtox (cytotoxicity in bacteria), and CAMVA (inflammation/toxicity). The results of the study indicated that, in general, the cytotoxicity end points did not correlate well with the in vivo data. The BCO-P, CAMVA, and Eytex assays had the best overall concordance (88.9, 75.8, and 75.0%, respectively) with this set of compounds. Estimation of irritation potential based on structure-activity (TOPKAT) was possible for only approximately 50% of the compounds; however, the assay showed 100% sensitivity (i.e., no false negatives), but low specificity (i.e., negatives correctly identified only 54.5% of the time). These data suggest that for screening of chemicals of diverse structure and properties, the more mechanism-based assays, as opposed to general cytotoxicity assays, hold more promise and should be further evaluated.

Animal Testing Alternatives↗
PubMed1992

Evaluation of the utility of a standard history questionnaire in assessing the neurological effects of solvents.

Using a standard battery of medical surveillance questions, a study was undertaken to determine if an increase in reported neurologic symptoms was resulting from solvent exposure at a pharmaceutical research, development, and manufacturing site. The prevalence of positive responses to 13 interval history questions pertaining to neurological symptoms was compared between those enrolled in exposed surveillance programs (n = 840) and those enrolled in other, non-solvent exposed surveillance programs (n = 1,042). The ratio of positive responders between the exposed and unexposed groups was used to generate a relative prevalence ratio (RPR). No significantly elevated RPRs were seen when the analysis was adjusted for the confounding factors of age, sex, smoking, alcohol use, noise exposure, and number of interval histories. These results suggest that workplace solvent exposures in the employees studied did not appear to result in obvious neurologic symptoms. However, low-level neurotoxic exposures can cause asymptomatic or sub-clinical disorders. Therefore, more sensitive neurotoxic surveillance systems need to be developed.

Adult↗
PubMed1991

The effect of deuterium labeling on the genotoxicity of N-nitrosodimethylamine, epichlorohydrin and dimethyl sulfate.

Deuterated and non-deuterated N-nitrosodimethylamine, epichlorohydrin and dimethyl sulfate were evaluated for the ability to induce DNA single-strand breaks in rat hepatocytes as measured by alkaline elution. Non-deuterated nitrosodimethylamine induced twice the amount of DNA-strand breaks as the deuterated form. No evidence of a deuterium isotope effect was seen for the direct-acting alkylating agents epichlorohydrin and dimethyl sulfate.

Animals↗
PubMed1991

Quantitative assessment of a human carcinogenic potency for propylene oxide.

The potential for causing carcinogenic and mutagenic effects is the main concern when assessing the risks associated with low-level exposures of humans to the industrially important epoxide, propylene oxide (PO). The available basic information used in estimation of carcinogenic risk has been reviewed. It is concluded that the published data from gavage studies in rodents are less appropriate and that observed cancer incidences from long-term inhalation should preferably be utilized for quantitative risk assessment. Furthermore, PO and ethylene oxide (EO) are directly acting alkylating agents which exhibit several similarities. Although data are less comprehensive for PO than for EO, PO appears to yield a rather uniform alkylation pattern in various tissues. Also, similarly to EO, PO is probably detoxified at a rate which does not vary widely in various mammalian species, including man. For these reasons, the surface-based extrapolation model for estimation of the human equivalent dose may not be appropriate, and the previously derived carcinogenic potency factors should be revised downward. Alternative risk estimates are provided. From the most relevant available studies, we propose a carcinogenic potency factor of 0.001 (mg/kg/day)-1 for PO in humans by inhalation.

Animals↗
PubMed1990

Evaluation of flu-like symptoms in workers handling xanthan gum powder.

A study was performed to determine the relationship between the handling of xanthan gum powder and reported symptoms. Nose and throat irritation was the most prevalent symptom, and the group with the greatest exposure reported the highest prevalence of nose and throat irritation as well as work-related illness. Employees who reported illness as a result of exposure to materials at work did not show a decrease in pulmonary function over the first day of the workday or workweek. There was no evidence of chronic loss of pulmonary function in employees with either the highest or longest exposure.

Adult↗
PubMed1988

Establishing airborne exposure control limits in the pharmaceutical industry.

In the course of employment, workers in the pharmaceutical industry are exposed to compounds which are designed to produce pharmacological effects. For the most part, exposure occurs in the handling of finely divided solids. Data from laboratory animal studies and clinical trials can be extrapolated to predict possible effects of exposure in the workplace. To that end a procedure for establishing workplace exposure control limits (ECLs) for pharmaceutical products is presented. Workplace exposure limits are given for 32 human health drugs.

Drug Industry↗
PubMed1987

The early and late effect of ultraviolet light exposure on the induction and repair of electron-induced DNA damage in rat epidermis.

Experiments were performed to determine the early and late effects of ultraviolet light (UVL) on induction and repair of DNA damage in rat epidermis by electron radiation. The dorsal skin of 28-day-old rats was irradiated with 8.0 X 10(5) or 13.6 X 10(5) ergs/mm2 UVL or weekly exposures of 0.4 X 10(5) ergs/mm2 UVL for 23 or 48 weeks. At 1, 48, 100, 200, or 400 days after single UVL doses or 28 days after last weekly UVL dose, the animals were irradiated with 1200 rads of electrons and the resultant alkaline labile DNA damage and repair quantitated by the S1 nuclease assay. The cytotoxic effect of UVL on basal epidermal cells was assessed by the labeled doublets technique. Single UV doses were capable of inhibiting repair of electron induced DNA damage for up to 5 h, but did not have any measurable late effect (greater than 20 days) on the rate or extent of DNA repair. The rate of DNA repair in epidermal cells from animals exposed to weekly doses of UVL was more rapid than in age-matched controls. The UV doses used on these experiments were shown to be cytotoxic to a large proportion of the basal epidermal cells. The results indicate that exposure of the rat skin to single cytotoxic or multiple exposures of UVL did not accelerate the age related loss of DNA repair capacity.

Age Factors↗
PubMed1987

Radioautographic measurement of electron-induced epidermal kinetic effects in different aged rats.

We have previously shown that the ability of rat epidermal cells to repair electron-induced DNA damage decreases as a function of age. The present investigation was performed to examine the relationship between this finding and sensitivity of epidermal cells to the cytotoxic effects of the radiation. Male CD rats at ages 2, 28, 100, 200, 420, and 728 days were injected with [3H]-thymidine [( 3H]Thd) at a dose of 2 mu Ci/g body weight. One hour later, the rats were anesthetized and the dorsal skin irradiated with various doses of 0.8 meV electrons at a dose rate of 660 rads/min. At 24 h after irradiation, radioautographs were made of a sheet of epidermis that was separated by trypsinization from the underlying dermis. Labeled cells were scored either as singlets or doublets (adjacent labeled cells). The percent labeled cells and percent labeled cells as doublets were determined. The estimated labeling index (the proportion of cells labeled by a single exposure to [3H]Thd) of the epidermal basal layer decreased as a function of age. The slope of the semilog plot of the percent labeled cells as doublets as a function of electron dose indicates that the Do value decreases with increasing age. The results show, however, that the greatest difference in sensitivity occurs between 2-day (neonatal) and 28-day (pubescent) animals and again between 420-day (adult) and 728-day (senescent) animals.

Aging↗
PubMed1986

Genotoxic activity of m-nitrobenzaldehyde.

m-Nitrobenzaldehyde (MNB) was evaluated for mutagenic activity using the Ames microbial mutagenicity test and for its ability to induce DNA single-strand breaks in rat hepatocytes as measured by alkaline elution. MNB was tested in S. typhimurium strains TA1535, TA1537, TA1538, TA98, and TA100, both with and without pretreatment with liver microsomes (S9) isolated from rats pretreated with Aroclor 1254. MNB produced 2-fold or greater increases in revertants in TA1538, both with and without S9, and in TA100 with S9 only. A 2-fold increase in revertants was seen in TA98, but only at the highest dose tested which did not produce inhibition of background growth. MNB caused a greater than 3-fold increase in elution slope, with DNA alkaline elution assay, but only at highly cytotoxic doses and, therefore, is not considered genotoxic in this system. It is concluded that MNB possesses weak genotoxic activity.

Animals↗
PubMed1986

Hazard evaluation of monochloroacetone.

Monochloroacetone was introduced in 1914 as a war gas, and presently it has a number of uses as a chemical intermediate. Apart from its biological properties as a lacrimator and vesicant, it is not a well-studied compound toxicologically. A series of acute toxicity studies were done using different routes of administration. An Ames mutagenicity test also was performed. These data were compared to manufacturing use information and data published in the literature. It is recommended that direct contact with liquid and vapor be prevented through strict engineering controls and that air concentrations be kept below 1 ppm as a ceiling concentration.

Acetone↗
PubMed1985

Repair of radiation-induced DNA damage in rat epidermis as a function of age.

The rate of repair of radiation-induced DNA damage in proliferating rat epidermal cells diminished progressively with increasing age of the animal. The dorsal skin was irradiated with 1200 rad of 0.8 MeV electrons at various ages, and the amount of DNA damage was determined as a function of time after irradiation by the method of alkaline unwinding followed by S1 nuclease digestion. The amount of DNA damage immediately after irradiation was not age dependent, while the rate of damage removal from the DNA decreased with increasing age. By fitting an exponential function to the relative amount of undamaged DNA as a function of time after irradiation, DNA repair halftimes of 20, 27, 69 and 107 min were obtained for 28, 100-, 200-, and 400-day-old animals, respectively.

Aging↗
PubMedDate not supplied

Respiratory effects of occupational exposure to an epoxy resin system.

A standardized respiratory questionnaire and pulmonary function tests were used to examine thirty-four employees of a snow-ski manufacturing plant, including twenty-five workers who were exposed to an epoxy resin system containing the amine hardener 3-dimethylamino propylamine (3-DMAPA). Maximum expiratory flow-volume curves were obtained on Monday and Thursday, before and after each shift, and FVC, FEV1.0, MEF50%, and MEF25% were caculated. Environmental measurements of the total amine levels were found to range from 0.41 to 1.38 ppm. The group with the greatest exposure (0.55-1.38 ppm) showed significant decreases in lung function over Monday and over the week. Although all employees in this group showed decreases in pulmonary function, acute changes were greater in present cigarette smokers and in subjects who reported respiratory symptoms upon exposure to the epoxy resin system. There was no evidence of permanent loss of lung function in subjects with either the highest or longest exposure.

Adult↗
PubMedDate not supplied

Setting occupational exposure limits for pharmaceuticals.

The active ingredients used in the pharmaceutical industry's products are designed to modify biological processes; thus, if not adequately controlled, they can place employees at risk. This chapter provides an historical look at the need for occupational exposure limits, as well as an overview of the limit-setting process.

Animals↗