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T S Davies

Publications and source records attributed to T S Davies.

16 recordsLinked to original sources
PubMed1998

Preclinical toxicological evaluation of sertraline hydrochloride.

The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drug-treated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk.

Adenoma↗
PubMed1998

Preclinical toxicological evaluation of sertraline hydrochloride.

The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with other serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drugtreated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk.

1-Naphthylamine↗
PubMed1995

The case for an upper dose limit of 1000 mg/kg in rodent carcinogenicity tests.

We examined two rodent carcinogenicity data bases comprising 301 chemicals from the US National Toxicology Program (NTP) and 241 pharmaceuticals from the US Physicians' Desk Reference (PDR) to determine the nature of the tumors produced at dose levels > 1000 mg/kg (or equivalent dietary concentrations). Ten chemicals increased tumors only at dose levels greater than 1000 mg/kg. For six of these, the lowest dose tested was > 1000 mg/kg, so they may be active at dose levels below 1000 mg/kg. One chemical was active in rats and mice, 2 in rats only and 7 in mice only. Four of the chemicals were mutagenic to Salmonella. The tumor types produced by the other six putatively non-genotoxic chemicals suggest that a high dose limit of 1000 mg/kg is appropriate for rodent bioassays. Overtly genotoxic chemicals are no longer routinely subjected to bioassays.

Animals↗
PubMed1994

The rodent carcinogenicity bioassay produces a similar frequency of tumor increases and decreases: implications for risk assessment.

We examined the overall results of 124 consecutive rodent carcinogenesis assays carried out at the maximum tolerated dose on 37 chemicals reported recently by the Toxicology Program of the United States. In 31 experiments each in male and female F-344 rats and in male and female B6C3F1 mice, tumor increases and decreases occurred in 41 and 46% of the experiments, respectively. In 22 experiments both increases and decreases in tumor incidence were reported. Of the experiments with decreases in tumor incidence, about 70% were associated with lower body weights of the treated animals. However, of the 30 chemicals producing some tumor decreases, 12 showed decreases in some experiments without any association with bodyweight. Ten chemicals that were Salmonella positive produced increases and decreases in tumor incidences and three produced only decreases in tumor incidence. If it is considered that the bioassay provides information relevant to the carcinogenic potential of a chemical, then logically it must also be considered that information about the cancer-preventive potential of a chemical is provided. When a chemical causes increases and decreases in tumors, several questions follow. First, which are more relevant to the health of an exposed individual: tumor increases or tumor decreases? Second, should such a chemical be stigmatized as a "carcinogen," in view of all the legal and economic implications that ensue from such a label? Third, how should one define a carcinogen?

Animals↗
PubMed1993

High dose levels are not necessary in rodent studies to detect human carcinogens.

Guidelines for the conduct of rodent carcinogenicity studies stipulate that when the test substance is administered via the diet, its concentration need not exceed 5% of the diet. Since it is now apparent that human carcinogens are amongst the most potent of rodent carcinogens, it should be possible to detect accurately potential human carcinogens by using only relatively low dose levels in rodent studies. Our analysis of the potency of human carcinogens in rodent studies leads to the conclusion that, even after applying a safety factor of 10, there is no purpose in using dose levels higher than 500 mg/kg body weight or 1% in the diet.

Animals↗
PubMed1982

Dose-response studies in carcinogenesis by nitroso-N-methyl-N-(2-phenyl)ethylamine in rats and the effects of deuterium substitution.

A dose-response study of the carcinogenicity of nitroso-N-methyl-N-(2-phenyl)ethylamine was carried out in male Fischer 344 rats. The compound was given in drinking water at concentrations of 115, 28, 9.5, 3.2, 1.1 and 0.4 mg/litre. The highest concentration proved toxic leading to the early death of several animals; the remainder of this group were treated for 21 wk. All of the other concentrations were given for 33 wk, except the 28 mg/litre treatment which ceased at 30 wk. An additional group of rats was given 0.4 mg/litre for 104 wk. In all groups of animals, except those in the high-dose group that died early and those given 0.4 mg/litre for 33 wk, 50% or more of the animals had tumours of the oesophagus or forestomach or both when they died. In several groups the number of rats with these tumours approached 100%. The total dose of carcinogen received by the rats in the lowest dose group was 1.3 mg and 45% of them had tumours of the upper gastro-intestinal tract. The effect on carcinogenicity of labelling the nitrosamine with deuterium in either the methyl group or the alpha-methylene of the phenylethyl group was determined by treating groups of rats with equimolar concentrations of the deuterium-labelled and unlabelled nitrosamine. A very significant increase in carcinogenic effectiveness was observed with the compound containing deuterium in the alpha-methylene of the phenylethyl group, suggesting that methylation might not be the important event in carcinogenesis by this compound in rats.

Animals↗
PubMed1982

Dose-response studies with nitrosoheptamethyleneimine and its alpha-deuterium-labeled derivative in F344 rats.

A dose-response study of the carcinogenicity of nitrosoheptamethyleneimine (N-HEP) in inbred F344 male and female rats was performed by administration of the nitrosamine at several concentrations in drinking water to groups of 20 rats. The concentrations differed by a factor of nearly 2.5 and ranged from 1.0 to 100 mg/liter. The duration of treatment was 13, 25, 50, or 100 weeks, after which the animals were allowed to die naturally of tumors induced. In most treated groups the incidence of tumors of the upper gastrointestinal tract approached 100%. However, at the higher doses there was an inverse relationship between total dose and survival time of the rats. Matched treatment of groups of rat with N-HEP labeled with deuterium in the alpha positions resulted in longer survival. The slower action of the deuterium-labeled compound, as measured by a lower rate of death from tumors, suggests that cleavage of a carbon-hydrogen bond at an alpha position is a rate-limiting step in carcinogenesis by N-HEP in rats.

Animals↗
PubMed1977

Pathology of subacute methylmercurialism in cats.

Clinical signs of toxicosis, neurologic lesions, and increased tissue residues of methylmercury (MM)were produced in 9 cats by oral administration of 1.29 and 0.86 mg of Hg/kg of body weight/day as methylmercuric hydroxide. Clinical signs, which began after 15 days of exposure, included anorexia, ataxia, hypermetria, proprioceptive impairment, blindness, vertical nystagmus, and grand mal convulsions. Significant lesions occurred in cerebrum, brainstem, and cerebellum and correlated well with clinical signs. Microscopic central nervous system lesions consisted of neuronal degeneration, necrosis and loss of neurons, swollen axons, demyelination, loss of nerve cell processes, vacuolation of neuropil, gliosis, neuronophagia, perivascular cuffs, endothelial hypertrophy and hyperplasia, leptomeningitis, and infrequent vascular necrosis. Overall distribution of central nervous system lesions was unrelated to daily dose, but more advanced lesions were produced by the smaller daily dose. Mean tissue residues of MM were generally directly related to daily dose, and the average distribution among tissues was constant, with highest concentrations in liver, followed by kidney, spleen, muscle, and brain. In utero exposure of kittens to MM, revealed transplacental accumulation.

Animals↗
PubMed1976

The pathology of subacute methylmerculialism in swine.

Clinical signs of toxicosis, neurologic lesions, and elevated tissue residues of methylmercury (MM) were produced in 12 pigs by oral administration of 1.29, 0.86, 0.64, and 0.43 mg mercury/kg of body weight daily as methylmercuric hydroxide (MMH). Clinical signs which began on day 17 were ataxia, dysmetria, blindness, convulsions, paresis, and death. Time of onset of signs was inversely related to size of daily dose. Microscopic lesions were found in the cerebrum brain stem, and spinal cord, and correlated well with clinical signs. The cerebrum in which severity of lesions was directly related to length of exposure was the most severely affected region of the central nervous system (CNS). Lesions were neuronal necrosis, neuronophagia, cortical vacuolation, axon swelling, gliosis, leptomeningitis, and vascular fibrinoid necrosis. Neuronal necrosis was most extensive within mid and deep cerebrocortical laminae. Brain residues of MM were directly proportional to the size of daily dose, and statistically significant. Distribution of MM among different tissues was rather uniform with highest concentrations found in liver, followed by kidney, muscle, spleen, and brain.

Animals↗
PubMedDate not supplied

Rodent carcinogenicity tests need be no longer than 18 months: an analysis based on 210 chemicals in the IARC monographs.

The IARC Monographs (Vols 1-70) were studied to determine the time of onset of treatment-related tumorigenicity in long-term rodent studies for chemicals classified by IARC as having sufficient evidence of carcinogenicity in animals. The analysis excluded studies on metals and their salts, studies on particulates, studies by parenteral routes of administration that resulted in tumours only at the site of exposure, and studies that did not approximate to the current standard long-term rodent carcinogenicity bioassay, for instance transplacental or multigeneration studies, initiator-promoter studies, lung tumour assays in Strain A mice and studies in newborn animals. Data from a total of 210 chemicals revealed that, overall, evidence of treatment-related tumorigenicity was first apparent within 12 months for 66% of the chemicals and for only 7% were studies of longer than 18 months necessary. All IARC Group 1 chemicals were detected in animals within 18 months, and most within 12 months. Most of the tumour types that required more than 18 months for detection were of dubious relevance to human risk assessment. Termination of rodent carcinogenicity studies at 18 months or earlier would greatly reduce the complications that arise in interpreting the findings in aged animals which often have defective hepatic or renal function and would also markedly reduce the time required for histopathological examination of dozens of tissues taken from the approximately 500 animals routinely employed in these studies.

Animals↗