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E Whorton

Publications and source records attributed to E Whorton.

7 recordsLinked to original sources
PubMed1998

Recommendations for statistical designs of in vivo mutagenicity tests with regard to subsequent statistical analysis.

A workshop was held on September 13 and 14, 1993, at the GSF, Neuherberg, Germany, to start a discussion of experimental design and statistical analysis issues for three in vivo mutagenicity test systems, the micronucleus test in mouse bone marrow/peripheral blood, the chromosomal aberration tests in mouse bone marrow/differentiating spermatogonia, and the mouse dominant lethal test. The discussion has now come to conclusions which we would like to make generally known. Rather than dwell upon specific statistical tests which could be used for data analysis, serious consideration was given to test design. However, the test design, its power of detecting a given increase of adverse effects and the test statistics are interrelated. Detailed analyses of historical negative control data led to important recommendations for each test system. Concerning the statistical sensitivity parameters, a type I error of 0.05 (one tailed), a type II error of 0.20 and a dose related increase of twice the background (negative control) frequencies were generally adopted. It was recommended that sufficient observations (cells, implants) be planned for each analysis unit (animal) so that at least one adverse outcome (micronucleus, aberrant cell, dead implant) would likely be observed. The treated animal was the smallest unit of analysis allowed. On the basis of these general consideration the sample size was determined for each of the three assays. A minimum of 2000 immature erythrocytes/animal should be scored for micronuclei from each of at least 4 animals in each comparison group in the micronucleus assays. A minimum of 200 cells should be scored for chromosomal aberrations from each of at least 5 animals in each comparison group in the aberration assays. In the dominant lethal test, a minimum of 400 implants (40-50 pregnant females) are required per dose group for each mating period. The analysis unit for the dominant lethal test would be the treated male unless the background frequency of dead implants (DI) is so low that multiple males would need to be integrated to meet the minimum observation of one adverse outcome (DI) per analysis unit. A three-step strategy of data analysis was proposed for the cytogenetic assays. Use of negative historical controls was allowed in certain circumstances for interpretation of results from micronucleus tests and chromosomal aberration tests.

Animals↗
PubMed1991

Factors contributing to chromosome damage in lymphocytes of cigarette smokers.

Cigarette smoking is generally believed to be responsible for a substantial number of human health problems. However, the causal relationship between smoking, the induction of biological effects and the extent of health problems among smokers have not been fully documented. Using the recently developed lymphocyte micronucleus (MN) assay, we have evaluated the chromosome aberration frequencies in 67 cigarette smokers and 59 matched non-smoking control subjects. We found that the mean MN frequency (per 100 cells) in the smokers was slightly higher than that found in the non-smokers (0.71 +/- 0.23 and 0.58 +/- 0.05 respectively; p less than 0.08). Factors which contribute to the expression of chromosome aberrations were also investigated. A significant age-dependent increase in MN frequencies was observed in both groups (p less than 0.05). Linear regression analysis showed that the age-dependent effects among smokers (r = 0.54; p less than 0.02) was further enhanced by cigarette consumption (r = 0.62; p less than 0.005). Consumption of low potency 'one-a-day' type multivitamins had no effect on MN frequencies in either sex of non-smokers and in the 1 male smoker who took multivitamins but vitamin intake consistently reduced the MN frequencies among female smokers. Using a challenge assay, fidelity of DNA repair was evaluated. Lymphocytes from both smokers and non-smokers were irradiated with single doses of 0 or 100 cGy of X-rays or with double doses of 100 cGy of X-rays each separated by 15 or 60 min (100/15 or 100/60). Chromosome translocation frequencies were consistently higher after irradiation in lymphocytes from smokers than in those from non-smokers. Statistically significant differences were detected when the cells were irradiated with the double doses of 100 cGy X-rays each separated by 60 min (p less than 0.05). These data suggest that lymphocytes from smokers made more mistakes in the repair of DNA damage than cells from non-smokers. Our studies provide new insights into the genotoxic effects of cigarette smoke and new information which may be useful for understanding the mechanisms for induction of health problems from smoking.

Aging↗
PubMed1987

A guide for mutagenicity testing using the dominant lethal assay.

The dominant lethal assay has been used and continues to be used to provide information about the effects of chemicals on the gonadal cells of male animals. Guidelines for conducting this test are useful but as with any guideline scientists should avoid interpreting them as protocols. Thus this document is a general approach to dominant lethal testing and should be used in conjunction with other available protocols and procedures.

Animals↗
PubMed1986

Genetics and smoking-associated cancers. A study of 485 families.

Cancer risk was evaluated in relatives of 254 consecutively ascertained probands with histologically verified lung cancer, and 231 probands with other smoking-related cancers. Findings disclosed a lack of any strong evidence for increased risk in lung cancer per se when only lung cancer in relatives was considered. Confounding factors, most prominent of which was the effect of cigarette smoking, variation of secular trends, and the heritability of the smoking phenotype itself, tended to obfuscate identification of an inherited effect presenting itself exclusively as lung cancer liability. On the other hand, a significant increase was observed in cancers of all anatomic sites among the relatives of lung cancer probands (P less than 0.001). Most of these neoplastic lesions were not associated with smoking and were not greatly influenced by secular trends. Furthermore, no significant excesses of cancer at all anatomic sites in relatives of probands with other smoking-associated carcinomas were observed. Thus, it may be concluded that the observation of increased risk for cancer at all anatomic sites in relatives of lung cancer probands may be a reflection of an underlying susceptibility to malignancy in these families.

Epidemiologic Methods↗
PubMed1986

Quantitative glomerular morphology of the normal and diabetic baboon kidney.

This is a study of quantitative glomerular morphology in 14 normal and 6 long-term diabetic female baboons between 3 and 25 years of age. In the normal female baboon, peripheral glomerular capillary basement membrane thickness increased until around 10 years of age, reached a plateau between 10 and 20 years of age, and possibly decreased at 25 years of age. Mean value for young (3 to 7 years of age) and older (10 to 25 years of age) controls were 266 nm and 329 nm respectively. Fractional volumes of mesangial matrix (8.9%) and mesangial cells (6.8%) were not affected by age. Glomerular basement membrane thickness and the volume of mesangial matrix increased progressively in female baboons with poorly controlled pancreatectomy-induced diabetes, while the volume of mesangial cells remained unchanged. After 106 to 145 months of diabetes, glomerular basement membrane thickness and the volume of mesangial matrix were 558 nm and 18.7% respectively. These values were significantly greater than those of the age-matched controlled (p = less than 0.05). By light and electron microscopy, the normal baboon glomerular morphology, morphometric measurements and changes with age were similar to those in man. The renal changes in diabetic baboons were also similar in morphology and rate of development to those of mild to moderate diffuse diabetic glomerulosclerosis in humans, indicating that the baboon is an ideal model for the long-term study of diabetic glomerulosclerosis. The presence of considerable interanimal variability in the degree of glomerulosclerosis attained after prolonged diabetes suggested that glomerulosclerosis progressed at different rates in these models. The reason for this was not apparent.

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