Carcinogenicity studies limitations

S1 C(R1) Dose Selection for Carcinogenicity Studies of Pharmaceuticals Limit Dose S2A Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals S2B Genotoxicity A Standard Battery for Genotoxicity Testing of Pharmaceuticals Toxicokinetics and Pharmacokinetics... 

SICa Guidance on Dose Selection for Carcinogenicity Studies of Pharmaceuticals Addendum on a Limit Dose and Related Notes Availability Notice Dec 97... 

The ideal species for carcinogenicity bioassays should absorb, metabolize, and excrete the compound under study exactly as humans do. Unfortunately, because of the small number of species that meet the other criteria for selection, there is limited practical utility to this important scientific concept, as applied to carcinogenicity studies. 

Skin studies have indicated that phenol can act as a promotor following treatment with a polyaromatic hydrocarbon (Boutwell and Bosch 1959 Salaman and Glendenning 1957). These studies are limited because phenol was administered in benzene (Boutwell and Bosch 1959) or acetone (Salaman and Glendenning 1957). An additional dermal carcinogenicity study in which phenol is administered in water is necessary to predict the carcinogenicity of phenol following dermal exposure. 

Not all of the biochemical events in this complex pathway from PPAR-alpha activation to tumors are completely understood, but much is known. It seems that at least some peroxisome-proliferating chemicals that also produce tumors in rodent livers do so through this pathway. If it can be demonstrated that such a mechanism is at work, then it seems that the risk of tumorigenicity for such compounds would be limited to doses that are sufficient to activate PPAK-alpha sufficiently to initiate the dangerous cascade of events within the cell. Experts have developed a number of experimental criteria that should be met if a compound is to be put in this class of carcinogens. Study of P PAR-alpha activation as a route of carcinogensis is an extremely active area of research. 

For discrete responses, the BMR is typically chosen at 10% above the control response, the BMD 10 as an excess risk of 10% is considered to be at or near the limit of sensitivity in most carcinogenicity studies and in some noncarcinogenicity studies as well. If a study has greater than usual sensitivity, then a lower BMR can be used, although the BMDio and BMDLio should always be presented for comparison purposes. 

Allyl alcohol was not carcinogenic in limited oral studies in rats and hamsters. It was mutagenic in bacterial assays and in mammalian cells in culture." ... 

Although a number of epidemiological studies have reported an increased risk of lung cancer among occupationally exposed beryllium workers, deficiencies in the studies limit any unequivocal conclusion. Specific criticisms concern the lack of consideration of latent effects, of smoking history, and of exposure to other potential carcinogens and the underestimation of expected lung cancer deaths in comparison populations. "... 

In a carcinogenic study, male and female rats were given DMHP by gavage 5 days/week for 103 weeks. At 200mg/kg, there were increases in alveolar/bronchiolar carcinomas, squamous cell carcinomas of the lung, and carcinomas of the stomach in male rats. Neoplastic lesions did not occur in mice after similar treatments. Species-dependent differences in the metabolism of DMPH were limited to more rapid metabolism and elimination by mice compared with rats. Therefore, the... 

Information on carcinogenic effects of PBDEs in animals is limited to results of chronic bioassays of decaBDE mixtures in rats and mice (Kociba et al. 1975 Norris et al. 1975b NTP 1986). As summarized below, these studies provide limited evidence for the carcinogenicity of decaBDE in animals. No carcinogenicity studies of octaBDE or pentaBDE were located in the available literature. 

Chloroacetonitrile was tested in a limited carcinogenicity study in female Senear... 

Dichloroacetonitrile was tested in a limited carcinogenicity study in female SEN mice by skin application, in an initiation/promotion study in female SEN mice by skin application and in a screening assay for lung tumours in female strain A mice by oral administration. No skin tumour was produced after skin application in mice or in the initiation/promotion study, in which dichloroacetonitrile was applied topically as six equal doses over a two-week period, followed by repeated doses of 12-0-tetradecanoyl-phorbol 13-acetate for 20 weeks. There was no increase in either the proportion of mice with lung tumours or the number of lung tumours per mouse (lARC, 1991). 

ICH S1C(R1). Dose Selection for Carcinogenicity Studies of Pharmaceuticals and Limit Dose. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 17 July 1997, November 2005. 

It is expected that patients may continue treatment of T-20 beyond 6 months, the treatment duration limit beyond which carcinogenicity studies for conventional pharmaceutical agents are generally needed. But, HIV patients have limited treatment options and the benefit-risk ratio for T-20 is considered extremely high, regardless of the outcome of animal carcinogenicity studies... 

ISO 10993 testing is intended to evaluate materials such as metals and polymers that essentially do not interact directly with the human immune system. However, the presence of an antibody on the device surface introduces the potential for cross-species reactions that may not be indicative of performance in humans. These interactions may affect some or all ISO 10993 in vivo tests. For example, the duration of chronic toxicity testing may be limited based on induction of immune responses or carcinogenicity studies may not be appropriate based on the specific product attributes of the antibody. 

SIC Carcinogenicity Dose selection for carcinogenicity studies of pharmaceuticals Dose Selection for Carcinogenicity Studies of Pharmaceuticals Addition of a Limited Dose and related Notes CPMP/ICH/383/95 Step 5... 

In determining the high dose for carcinogenicity studies, it may not be necessary to exceed a dose of 1500 mg/kg/day. This limit dose applies only in cases where there is no evidence of genotoxicity and where the maximum recommended human dose does not exceed 500 mg/day. 

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