Search PubMed⌕ Search

Biomedical subjects

D R Mattison

Publications and source records attributed to D R Mattison.

At least 55 records · Page 3Linked to original sources
PubMed1990

The role of epoxidation in 4-vinylcyclohexene-induced ovarian toxicity.

4-Vinylcyclohexene (VCH) is present in gases discharged during synthetic rubber production. Chronic treatment of B6C3F1 mice and F-344 rats with VCH by gavage has been shown to induce ovarian tumors in mice but not in rats. Our objective was to understand the mechanism of the species difference in VCH-induced ovarian tumors. Since a critical step in the induction of ovarian tumors is destruction of the small oocyte, small oocyte counts obtained from serially sectioned ovaries were used as an index of toxicity. VCH or its epoxide metabolites [VCH-diepoxide, VCH-1,2-epoxide, and VCH-7,8-epoxide (in mice only)] were given to 28-day-old female mice and rats in corn oil, ip, at doses ranging from 0.07 to 7.4 mmol/kg body wt/day for 30 days. The dose which reduced the small oocyte count to 50% that of control was defined as the ED50. In mice, the ED50 for the reduction in small oocytes by VCH was 2.7 mmol/kg, whereas, no detectable oocyte loss occurred in rats at the highest dose of VCH (7.4 mmol/kg). The potency of the epoxides of VCH was greater than that of VCH in both species. The ED50 for oocyte loss by VCH-1,2-epoxide in mice and rats was 0.5 and 1.4 mmol/kg, respectively. In mice, VCH-7,8-epoxide had comparable potency to VCH-1,2-epoxide (ED50 = 0.7). VCH diepoxide was even more potent with ED50 values of 0.2 and 0.4 mmol/kg, in mice and rats, respectively. The dose response of the blood concentration of VCH-1,2-epoxide in mice after VCH showed that doses of VCH which caused minimal toxicity had the lowest blood level of this ovotoxic epoxide. Pretreatment of mice with the cytochrome P450 inhibitor chloramphenicol (200 mg/kg, ip) inhibited VCH epoxidation in vivo and in vitro and partially protected mice from VCH toxicity. Thus it appears that metabolism of VCH to epoxides and their subsequent destruction of oocytes are critical steps in VCH-induced ovarian tumors. Rats may be resistant to ovarian tumor induction by VCH because the amount of VCH converted to epoxides is insufficient to produce oocyte destruction.

Animals↗
PubMed1990

Eliciting principles of hazard identification from experts.

National experts in the field of developmental toxicology were interviewed in order to elicit the principles, or rules-of-thumb, they use in determining if a compound or agent is likely to be a developmental hazard during pregnancy. Several levels of individual and cumulative consensus activity were carried out that resulted in consensus in 71 rules and partial consensus in an additional 24 rules of 145 rules initially elicited. Rules could be divided generically into those affecting the expert's confidence in a piece of scientific evidence and those determining the weight of importance of that evidence in deciding about hazard identification. Topically, the rules also divided into those about the general nature or characteristics of a compound, animal studies testing for an effect of the compound, and human reports about the presence of absence of developmental effects associated with the compound. Several conclusions about the methodology include the following: 1) expert systems must be based on the knowledge of more than one expert; 2) considerable human effort is expended in evaluating the certainty of scientific evidence before combining the evidence for problem solving; 3) how experts use evidence of different degrees of uncertainty in their decisions is a major area that is yet to be determined and that may greatly affect subsequent efforts in artificial intelligence; and 4) knowledge elicitation by interview has limitations but is a workable methodology for medical decision making.

Animal Testing Alternatives↗
PubMed1990

Reproductive toxicity: male and female reproductive systems as targets for chemical injury.

On the basis of current knowledge of reproductive biology and toxicology, it is apparent that chemicals affecting reproduction may elicit their effects at a number of sites in both the male and the female reproductive system. This multiplicity of targets is attributable to the dynamic nature of the reproductive system, in which the hypothalamic-pituitary-gonadal axis is controlled by precise positive and negative feedback mechanisms among its components. Interference by a xenobiotic at any level in either the male or the female reproductive system may ultimately impair hypothalamic or pituitary function. Normal gonadal processes such as spermatogenesis or oogenesis, ejaculation or ovulation, hormone production by Leydig or granulosa cells, and the structure or function of the accessory reproductive structures (e.g., epididymis, fallopian tube) also appear vulnerable to xenobiotics. The reproductive system is a complex one that requires local and circulating hormones for control. This brief review illustrates a system for characterizing the mechanism of action of reproductive toxicants, as well as for defining the sites available for disruption of reproduction. Unfortunately, at present, data addressing the actual vulnerability of reproduction are sorely lacking. However, when experiments have been conducted and combined with epidemiologic data or clinical observation, it has been possible to demonstrate impairment of reproductive processes by xenobiotics. The role of environmental exposure to xenobiotics in the increase in infertility that has been observed remains to be defined.

Environmental Exposure↗
PubMed1989

Workshop on risk assessment in reproductive and developmental toxicology: addressing the assumptions and identifying the research needs.

The risk assessment process is an imprecise procedure aimed at determining a toxicant exposure level with an acceptable risk to the human population. The lack of precision is due to the uncertainties in the assumptions that must be made due to the lack of specific scientific information or knowledge of how to use certain types of data. Unfortunately, every necessary piece of information cannot be obtained for every chemical requiring a risk assessment. In order to better identify and understand some of the assumptions that are made in the risk assessment of reproductive and developmental toxicants, a workshop was organized to specifically define the assumptions underlying the risk assessments for seven specific toxicants (dibromochloropropane, dioxin, glycol ethers, heptachlor, lead, tetrahydrocannabinol, and vitamin A) and to determine the potential research which would reduce the uncertainty associated with making those assumptions. The major assumptions discussed centered around the topics of heterogeneous populations, thresholds, safety factors, exposure assessment, quantitative structure-activity relationships, and mechanisms. This report is the summary of the workshop discussions.

Animals↗
PubMed1989

Criteria for identifying and listing substances known to cause developmental toxicity under California's Proposition 65.

Because of the automatic restrictions and warning requirements imposed on substances identified by the state as "known to cause developmental toxicity," the Expert Committee recommends the use of criteria that emphasize human relevancy, biological plausibility, and evidence in support of a selective, adverse developmental effect at non-maternally-toxic doses. In many instances, data for substances of public concern will be insufficient at present to meet these criteria. The fact that a substance is not listed as "known to cause developmental toxicity" does not create a presumption that the substance is safe. The Expert Committee, therefore, urges that these substances be recommended for further testing and that high priority be given to conducting the necessary tests. The Expert Committee reiterates its concern that substances listed by the SAP be identified according to the toxic endpoints (cancer, male reproductive toxicity, female reproductive toxicity, and/or developmental toxicity) that led to listing. Further, the Expert Committee recommends that the state Health and Welfare Agency institute education programs emphasizing appropriate courses of action for citizens informed of exposures to substances known to the state to cause cancer, birth defects, or reproductive toxicity.

Animals↗
PubMed1989

Ovarian toxicity of benzo(a)pyrene and metabolites in mice.

The effect of intraovarian injection of benzo(a)pyrene (BP) or one of three metabolites: +7,8-oxide (7,8-O), (-)-dihydrodiol (DHD), and (+)-diol-epoxide-2 (DE2) on ovarian volume, weight, and follicle number was investigated in DBA/2N (D2), C57BL/6N (B6), and (DBA/2N x C57BL/6N)F1 (F1) mice. Female mice, 6 to 8 weeks old, were treated by injection into the right ovary with the indicated compound (10 micrograms in 1 microL DMSO). The left ovary was untreated. Two weeks following treatment both ovaries were removed, fixed in Bouin's medium, serially sectioned, and stained with hematoxylin and eosin. Right ovarian weight was decreased in D2 mice treated with BP (P less than 0.01 and DHD (P less than 0.01). Left ovarian weight was increased in D2 mice treated with DE2 (P less than 0.05). BP decreased right ovarian volume in D2 (P less than 0.01) and F1 (P less than 0.01) mice. 7,8-O decreased right ovarian volume in D2 mice (P less than 0.05). DHD decreased right ovarian volume in D2 (P less than 0.01) and F1 (P less than 0.05) mice. DE2 decreased right ovarian volume in D2 (P less than 0.01) and F1 (P less than 0.01) mice. Left ovarian volume was increased in B6 (P less than 0.01) and D2 (P less than 0.05) mice treated with DE2. The number of small follicles was decreased in D2, B6, and F1 mice treated with DE2 (P less than 0.01). BP and DHD also decreased small follicle number in D2 and F1 mice (P less than 0.01). The number of growing follicles was decreased in B6, D2, and F1 mice treated with DE2 (P less than 0.01). Treatment with DHD decreased the number of growing follicles in D2 mice (P less than 0.05). The number of antral follicles was reduced in F1 mice treated with BP (P less than 0.05), DHD (P less than 0.01), and DE2 (P less than 0.01). The number of antral follicles was also reduced in B6 mice treated with DE2 (P less than 0.01) and in D2 mice treated with DHD (P less than 0.05) and D2 mice treated with DE2 (P less than 0.01). These experiments suggest that toxic effects to one ovary may result in compensatory hypertrophy of the contralateral ovary. Morphometric analysis of the ovary, including ovarian volume, represents a useful objective measure of ovarian toxicity.

Animals↗
PubMed1989

The mechanisms of action of reproductive toxicants.

Successful human reproduction is a complex process which requires normal function of 2 individuals. Reproductive toxicants can impair reproduction by acting in the male, female or both. Reproductive toxicants can produce their adverse effects by several direct and indirect mechanisms. The mechanisms by which reproductive toxicants impair reproduction are reviewed.

Animals↗
PubMed1989

Prediction of risk for human developmental toxicity: how important are animal studies for hazard identification?

To determine how developmental toxicity studies in animals can be used in human risk assessment, a data base was assembled from the literature. It included probable, suspected, unknown, and probably negative teratogenic or embryotoxic drugs and chemical compounds. For each of 175 substances, we recorded the results of any developmental toxicity testing in up to 14 animal species and any reports of mutagenicity or carcinogenicity. Logistic regression and discriminant analysis were used to predict a compound's effect in humans. A measure of the number of positive animal studies and bacterial mutagenicity were important predictors in both models, as were the specific results in hamsters and subhuman primates. The fact that a compound had been tested at all in subhuman primates was more important in predicting human risk than was the result itself. The methods used correctly classified the study compounds 63-91% of the time, depending upon how the suspicious and unknown compounds were treated. The models had a sensitivity of 62-75%, a positive predictive value of 75-100%, and a negative predictive value of 64-91%. These findings imply that studies in laboratory animals carry weight in predicting human developmental toxicity. The more animal species in which a compound is positive, the more likely it is to have a human effect, albeit not the same effect as in the animals. Clinicians should not ignore developmental toxicity tests in animals "because laboratory rats are not like humans."

Abnormalities, Drug-Induced↗
PubMed1988

An evaluation of the serum FSH as a biomarker for ovarian toxicity in the rat.

There is a need for a biomarker to evaluate numbers of oocytes in an ovary exposed to various exogenous toxicants. Experiments that had been previously reported were reviewed to assess the serum FSH as such a biomarker. Rats that had been exposed to direct ovarian radiation and direct ovarian radiation with cyclophosphamide were reviewed to ascertain the relationship of follicle numbers to the serum FSH. Under the conditions of reduced serum estrogen, linear regression analysis indicated that the serum FSH correlated best with the calculated volume of antral follicles. Receiver operating characteristic curves were calculated to determine that an elevation of the serum FSH two standard deviations above the mean had the greatest diagnostic power in predicting a significant loss in both the number of healthy follicles and the calculated volume of healthy antral follicles. The serum FSH as a biomarker appears to have utility as a measure of the ovarian content of healthy antral follicles rather than as a measure of the total number of oocytes alone.

Animals↗
PubMed1988

Transport and metabolism of dexamethasone in the dually perfused human placenta.

Dexamethasone (DEX), a synthetic glucocorticoid, has been suggested to accelerate fetal lung maturation and is sometimes used clinically during premature labor for this purpose. These experiments were initiated to measure the rate of transfer and metabolism of DEX by the human placenta. Lobules from full term (38-41 weeks) human placentas, obtained immediately after delivery, were perfused on both maternal and fetal sides. Radiolabeled (14C) DEX and tritiated water were infused into the maternal artery. Samples were taken at timed intervals throughout the perfusion period from the maternal artery (MA), maternal vein (MV), fetal artery (FA) and fetal vein (FV). Transport was determined by liquid scintillation spectroscopy and metabolism of DEX was determined by reversed phase HPLC. Tritiated water reached equilibrium between the maternal and fetal circulations within 75 min of perfusion, while total 14C-labeled radioactivity attained equilibrium after 180 min. HPLC revealed one metabolite of DEX which co-migrated with an 11-ketobetamethasone standard. The concentration of metabolite at 10, 30, 120, and 240 min in the FV were 9, 22, 40, and 41 ng/ml, respectively, and in the MV were 15, 28, 46, and 48 ng/ml, respectively. However, the ratio of metabolite/DEX was greater at 10 min in the FV (0.39) than in the MV (0.08). These data suggest that DEX crosses the human term placenta, that an enzyme in the placenta metabolizes DEX into an 11-keto-metabolite, and that a greater metabolite:DEX ratio is found at earlier times in the fetal circulation than in the maternal circulation.

Biological Transport↗