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PubMed1998

Genetic toxicology: impact on the next generation of toxicology.

In the early 1970s, we overestimated the range of applicability of the hypothesis that mutations were highly predictive of rodent cancer. Many substances that are nonmutagenesis in current screens are carcinogenic; some genotoxicants are not carcinogenic. Methods of quantitative risk assessment that were based on the 1970s' hypothesis of cancer induction are thus inherently limited. Current methods of classifying carcinogens and calculation of human risk must reflect recent understanding of the diversity of mechanisms of carcinogenicity. Screening for genotoxic potential has clearly helped to prevent highly toxic and high risk chemicals from being introduced into commerce. Additional attention, however, must now be focused on assessment and management of risk of those carcinogens and other toxicants that cause damage through mechanisms other than direct damage to DNA. While in the past we depended on the knowledge of chemists and genetic toxicologists to predict carcinogenic potential, on whom do we depend today? With the increasing complexity of our knowledge of the processes of carcinogenicity, it is likely that there will not be any single discipline that can meet the challenge. The more we learn, the more we will come to depend on a profile of information that encompasses the known mechanisms of cancer.

Animals↗
PubMedDate not supplied

Toxicological evaluation of an electrically heated cigarette. Part 4: Subchronic inhalation toxicology.

The biological activity of mainstream smoke from an electrically heated cigarette (EHC) with controlled combustion and from the University of Kentucky Reference Cigarette 1R4F was determined in Sprague Dawley rats exposed nose-only for 90 days, 6 h a day, 7 days per week. For an equivalent response comparison between the two cigarette types, two doses were chosen for the EHC where the anticipated results were in the dynamic range of the 1R4F dose-response curve (four concentrations) for most end points. The number of cigarettes smoked per m(3) of diluted smoke resulted in total particulate matter concentrations of 40 and 90 microg l (-1) for the EHC and 40-170 microg l (-1) for the 1R4F. Biomonitoring indicated achievement of target doses. Mainstream smoke yields were lower for the EHC, with the exception of formaldehyde. No smoke-related mortality, remarkable in-life observations or abnormal gross pathological findings were observed. Smoke- and dose-related clinical pathology and organ weight changes included: increases in segmented neutrophils, some liver parameters and lung and adrenal weight relative to body weight; and decreases in lymphocytes, glucose concentration and spleen weight. Smoke-related histopathological findings in the respiratory tract included epithelial cell hyperplasia, squamous metaplasia, atrophy and accumulation of pigmented alveolar macrophages; they were mostly dose-dependent, more pronounced in the upper than lower respiratory tract and completely or partially reversed by 6 weeks post-inhalation. Qualitatively, the biological effects seen for the EHC and the 1R4F were comparable and similar to those observed in other mainstream smoke inhalation studies. Quantitatively, the biological activity of the EHC mainstream smoke was, on average, 65% lower than that of the 1R4F mainstream smoke on an equal cigarette basis and equivalent activity on an equal TPM basis.

Administration, Inhalation↗
PubMed1996

The inhalation toxicology, genetic toxicology, and metabolism of difluoromethane in the rat.

Difluoromethane (HFC32) is under development as a replacement for chlorofluorocarbons (CFCs) in some refrigeration applications. It has been evaluated by standard studies of toxicity, developmental toxicity, and genotoxicity. In addition, the metabolism and disposition of HFC32 was investigated and a physiologically based pharmacokinetic (PB-PK) model constructed. Inhalation of HFC32 (up to 50,000 ppm) caused no organ-specific effects, but resulted in slight maternal toxicity to the pregnant rat and rabbit and some fetotoxicity to the rat. HFC32 did not sensitize the heart to adrenaline. The pharmacokinetics of [14C]difluoromethane (10,000 to 50,000 ppm/6 hr) revealed that about 2.1% of the inhaled HFC32 was absorbed and that steady state blood levels were achieved within 2 hr and were proportional to dose. Carbon dioxide was the major metabolite of HFC32 at all exposure levels. Carbon monoxide was not detected. The in vivo data were used to validate a PB-PK model to describe the uptake and metabolism of HFC32. Absorption and distribution are adequately described using rat blood:air and tissue:air partition coefficients. Metabolism, which was linear across the dose range, was described by a first order rate constant (Kf = 8.98 hr-1). Of the absorbed HFC32, about 63% was metabolized at all doses; however, when metabolism was expressed as a percentage of the inhaled dose it was much lower, being about 1.4% of the HFC32 entering the airways. Overall, the results indicate that HFC32 is of very low toxicity and should be an acceptable alternative to CFCs.

Animals↗
PubMed2001

ICCVAM evaluation of the murine local lymph node assay. Data analyses completed by the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods.

To evaluate the reliability of the murine local lymph node assay (LLNA), a test for allergic contact dermatitis activity, the inter- and intralaboratory consistency statistics (h and k, respectively) were calculated for validation studies testing multiple chemicals. The analysis indicated the absence of excessive variability in the dose calculated to induce a threefold or greater increase in the stimulation index (SI). To assess the appropriateness of using an SI of 3 as the decision criteria for identifying a sensitizing compound, LLNA results based on SI values of 2.0, 2.5, 3.0, 3.5, and 4.0 were compared with guinea pig or human results. The results supported the use of an SI of 3 as the decision criteria. Assay performance was determined by comparing LLNA results to results obtained for guinea pigs or humans. The accuracy of the LLNA was 89% when compared with results from the guinea pig maximization test (GPMT)/Buehler assay (BA). The performance of the LLNA and the GPMT/BA was similar when each was compared to human maximization test results plus substances included as human patch test allergens. The LLNA offered advantages over the GPMT in respect to both the time required to conduct the test and the assay cost.

Animal Welfare↗
PubMed1998

From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug.

NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4-hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.

4-Hydroxyphenylpyruvate Dioxygenase↗