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.

The putative carcinogenic risk to humans from ingestion of edible tissues containing traces of nongenotoxic veterinary drugs is so slight that the routine application of rodent cancer bioassays cannot be justified. This argument is based, first, on the pharmacological similarity of veterinary and human drugs: many of the latter that are carcinogenic to rodents have been deemed on mechanistic and/or potency grounds not to pose a cancer risk to humans. Second, the distribution of a veterinary drug through the target animal body before ingestion of a portion of edible tissue by humans days or weeks later means that the human dose from a residue is several orders of magnitude lower than the normal dose of human drugs. The dose of residue is also much lower than the exposure of humans to the most potent carcinogens.

The tissue residues of veterinary drugs given to food-producing animals are an ill-defined mosaic of parent drug and metabolites. Consumers are only ever exposed to this mixture in the presence of a vast excess of the excipient, food. Given the modifying effects of food on the absorption and disposition of co-administered xenobiotics, it follows that the toxicity of these residues can only be properly evaluated in the presence of a large excess of food. Adoption of a relay toxicity strategy addresses these two points. The proposed relay toxicity testing approach is as follows. The target species receives a recommended dosage regimen of the drug, but a dose level three- to five-fold higher than normal and the animals are then killed several days earlier than the projected withdrawal period. The tissues from these animals, containing the residue mixture at artificially high concentrations, are then administered to laboratory animals for conventional toxicological evaluation. In this approach the residues do not require individual identification and their potential toxicity is evaluated in the presence of the inescapable excipient, food. Determination of an 'exposure' level without observerable toxicity provides, in principle, the means of relating human safety to a No-Observed Effect Level in laboratory animals in the traditional manner.

Journal of Veterinary Pharmacology and TherapeuticsVolume 19, Issue 4 p. 312-312 The safety assessment of drug residues at injection sites D. M. GALER, D. M. GALER Pfizer Central Research, Groton, CT 06340, USASearch for more papers by this authorA. M. MONRO, A. M. MONRO Pfizer Central Research, Groton, CT 06340, USASearch for more papers by this author D. M. GALER, D. M. GALER Pfizer Central Research, Groton, CT 06340, USASearch for more papers by this authorA. M. MONRO, A. M. MONRO Pfizer Central Research, Groton, CT 06340, USASearch for more papers by this author First published: August 1996 https://doi.org/10.1111/j.1365-2885.1996.tb00055.xCitations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume19, Issue4August 1996Pages 312-312 RelatedInformation

Fluconazole is an orally active bis-triazole antifungal agent that acts by selective inhibition of lanosterol 14 alpha-demethylase, a key enzyme for maintenance of the fungal cell wall. It is not genotoxic. In a 2 year carcinogenicity study in Sprague-Dawley rats, fluconazole decreased mammary fibroadenomas in females and adrenal pheochromocytomas in males, and increased hepatic adenomas in males. The pattern of these changes is explicable in terms of a hormonal imbalance, corroborated in other studies with fluconazole in rats by changes in the weights of hormone-sensitive organs and circulating levels of 17 beta-estradiol. The decreases in mammary tumors are probably a consequence of aromatase inhibition by fluconazole at high dose levels. The tumor effects observed in this study are extremely unlikely to be of relevance to humans, since the hormone effects observed in this study do not occur in humans treated with therapeutic dose levels of fluconazole. This study illustrates the importance of seeking a mechanistic interpretation of rodent tumor findings, which may then be assessed for its relevance to the clinical use of a drug.

This study entails a pharmacoldnetic analysis of the relationship between the external dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD) and resulting concentrations of TCDD in internal tissues and organs of humans and rodent species. The methodology is based on the development and testing of physiologically based pharmacokinetic models for several rodent species and humans. The results indicate that the relationship between the external dose of TCDD and resulting TCDD concentrations in liver and adipose tissue of humans and various species of rats and mice can vary by as much as 725 fold, illustrating that humans and experimental animals differ considerably in their ability to convert external dosages of dioxin to tissue concentrations. Interspecies scaling factors are reported to express the differences in tissue concentrations of dioxin between mice, rats and humans in response to an equivalent external dose. The significance of these findings for conducting human cancer and ecological risk assessments is discussed. It is recommended that pharmacokinetic differences be considered explicitly in risk estimation, while separately recognizing interspecies differences in pharmacodynamics (sensitivity).

A classical dilemma in toxicology is how the dose administered relates to the dose delivered to the target site. Plasma concentrations of the test substance may be misleading since the concentration of any given substance in the plasma may not be representative of its concentration in tissues. Furthermore, a given tissue concentration of a xenobiotic can evoke responses which are highly species-dependent. While evaluating toxicity data within one species, plasma concentrations reflect the effects of route of administration, bioavailability, dose level, multiple dosing, age, gender, etc. However, when toxicity data is compared across species, the relevance of plasma concentrations depends on the nature of the toxicity. Reversible, pharmacodynamic effects often correlate with plasma concentrations, although there may be marked interspecies differences in dose-response relationships. Irreversible effects, if pharmacodynamic in origin, often correlate better with the intensity/duration of the pharmacodynamic response, rather than with plasma concentration. On the other hand, irreversible effects, if chemically mediated, may not correlate at all with plasma concentration, the lesions being caused by reactive metabolites of fleeting existence, which rarely survive long enough to leave their site of synthesis. They cannot be measured in the plasma nor predicted from plasma concentrations of the parent xenobiotic. The limitations of plasma concentrations in interpreting the toxicology of substances which are tissue-sequestered, which are subject to pharmacogenetic factors, or which show plasma concentrations that are not proportional to dose are also discussed. Mention is made of possible alternatives to plasma concentrations in assessing exposure in toxicology studies.

Male Sprague-Dawley rats received a single subcutaneous injection of phenoxybenzamine and each was allowed to mate with an untreated receptive female at 5, 29 or 53 h post-injection. At 5h the number of males ejaculating was reduced and fertility virtually abolished; at 29 h all males ejaculated, but fertility was still low; at 53 h the performance of the males was normal.

Studies were carried out to investigate the mechanism whereby the imidazole anti-fungal, tioconazole, affects parturition in rats. Administration s.c. of luteinizing hormone (LH) to pregnant rats on days 15-17 post-insemination (p.i.) or days 15-21 p.i. delayed the onset of parturition by a day and markedly reduced the ovarian production of 17 beta-estradiol, but not of progesterone. Administration of LH on days 18 and 19 p.i., which was already known to advance birth, reduced ovarian production of progesterone, but not of 17 beta-estradiol. The similarity of these results to those for tioconazole administered from days 15 p.i. or on days 18 and 19 p.i. suggests that tioconazole affects parturition in rats, at least in part, via LH.

Male Sprague-Dawley rats were treated with clofibrate (CLOF) in the diet for 2 years or with 4 i.p. injections of either diethylnitrosamine (DEN) or benzidine (BZ) followed by phenobarbital (PB) in the diet for 67 weeks, or just with PB for 41 weeks. Animals were killed at frequent intervals, some while still on treatment and others after 3 or 6 months withdrawal of treatment. The livers were subjected to cytochemical measurements of the parenchyma, foci, nodules and carcinomas. The parenchyma of the CLOF groups showed, in general, increases in glucose-6-phosphate dehydrogenase (G-6PD), alpha-glycerophosphate dehydrogenase (alpha-GPD), 5'-nucleotidase (5'-Nu), acid phosphatase (AP) and catalase and decreases in uricase and glutathione (GSH). CLOF induced a low incidence of GSH positive foci; nodules showed universally lower levels of catalase and GSH. In the DEN/PB and BZ/PB groups the parenchyma showed increases (even before PB treatment started) in G-6PD and in gamma-glutamyl transpeptidase (gamma-GT) and decreases in GSH. DEN raised and BZ lowered 5'-Nu. Neither initiator affected alpha-GPD. Both initiators caused a high incidence of foci positive for G-6PD and for gamma-GT; nodules induced by DEN/PB were mainly positive for gamma-GT and showed an erratic response to the other parameters. Carcinomas, found only after DEN/PB, were all positive for G-6PD and, with one exception, all were negative for alpha-GPD, 5'-Nu, AP and GSH. All changes regressed within 3 months of withdrawal of CLOF but not after withdrawal of PB from DEN-initiated animals. In conclusion G-6PD, alpha-GPD and 5'-Nu may be useful histocytochemical parameters for studying the precarcinogenic hepatic changes and nodules induced by peroxisome proliferators and by genotoxic hepatocarcinogens.

Tioconazole, an imidazole antifungal agent, was administered orally at 100 mg/kg/day to pregnant rats according to two regimens; in one, treatment started on day 15 post-insemination (p.i.) and in the other it started on day 18 p.i. The first regimen caused a delay in onset of parturition and a prolongation of labour. Serum progesterone was decreased from days 17 to 21 p.i., 17 beta-oestradiol decreased on day 21 p.i., LH increased on day 17 p.i., and the normal surge of prolactin on day 21 p.i. abolished. The parturition disorders disappeared when 17 beta-oestradiol (0.125 microgram/animal/day s.c.) was given with tioconazole from day 15 p.i. In the second regimen, tioconazole treatment advanced by about 24 hours the onset of parturition and the normal fall in serum progesterone and the surge in prolactin. Serum 17 beta-oestradiol was unaffected, but LH was raised on days 19 and 20 p.i. In animals receiving progesterone (2.5 mg/animal/day, s.c.) and tioconazole from day 18 p.i. parturition was no longer advanced. In conclusion, the parturition disorders observed in rats during tioconazole treatment are associated with a modification of progesterone and 17 beta-oestradiol serum levels. These findings have questionable relevance for the human situation as the roles of these steroid hormones in parturition in women are different from those in rats.

Dazoxiben, an orally active specific inhibitor of thromboxane synthetase, was administered by mouth daily to dogs and rats for 6 months. Dogs showed no evidence of toxicity up to 300 mg day-1 kg-1, the highest dose level used. Rats showed no evidence of toxicity after 100 mg day-1 kg-1, but at 300 mg day-1 kg-1 there were slight increases in plasma calcium and urea concentrations and a moderate incidence of focal nephrosis; males showed a slightly increased platelet count. Studies in rats and rabbits at dose levels up to 400 mg day-1 kg-1, by mouth, revealed no adverse effects on male or female fertility, embryogenesis, parturition or postnatal development. As dazoxiben is well absorbed after oral administration, the generally negative outcome to these toxicity studies suggests that selective inhibitors of thromboxane synthesis may be largely free of adverse effects which might impede their therapeutic or prophylactic use in clinical medicine.

Reproductive toxicology studies were conducted in rabbits and rats given piroxicam, a non-steroidal anti-inflammatory agent (NSAI), orally at 2, 5 and 10 mg/kg/day. In teratology studies there was neither drug-related embryotoxicity nor teratogenicity. As piroxicam, like other NSAI, affects parturition in rats and leads to a progressive toxicity in lactating females, standard protocols were modified: dams of the female fertility study were treated from 2 weeks prior to mating until day 6 of gestation and females of the post-natal toxicity study were treated from parturition until day 12 of lactation. No other adverse effects on reproduction, fertility and postnatal development were observed.