The use of structured frameworks can be invaluable in promoting harmonization in the assessment of chemical risk. IPCS has therefore updated and extended its mode of action (MOA) framework for cancer to address the issue of human relevance of a carcinogenic response observed in an experimental study. The first stage is to determine whether it is possible to establish an MOA. This comprises a series of key events along the causal pathway to cancer, identified using a weight-of-evidence approach based on the Bradford Hill criteria. The key events are then compared first qualitatively and then quantitatively between the experimental animals and humans. Finally, a clear statement of confidence, analysis, and implications is produced. The IPCS human relevance framework for cancer provides an analytical tool to enable the transparent evaluation of the data, identification of key data gaps, and structured presentation of information that would be of value in the further risk assessment of the compound, even if relevancy cannot be excluded. This might include data on the shape of the dose-response curve, identification of any thresholds and recognition of potentially susceptible subgroups, for example, the basis of genetic or life-stage differences.

This study characterized the electrical and mechanical activities of human colonic muscle strips obtained from either the ascending, descending or sigmoid colon of patient volunteers during elective colon resections. Rhythmic contractile activity was observed in colonic circular muscle strips in the absence of external stimuli. This activity persisted in the presence of atropine, phentolamine, propranolol, tetrodotoxin and Nω‐nitro‐L‐arginine but was abolished by nifedipine. The activity of whole circular muscle (WCM) was compared with that of the myenteric half (MCM), the submucosal half (SCM) and the interior (ICM) of the circular muscle layer. WCM exhibited a prominent 2–4 contractions min−1 contractile pattern which was also present in strips of SCM. In contrast, MCM and ICM exhibited slow (0.3–0.6 contractions min−1), long duration contractions with superimposed higher frequency contractions (17–18 contractions min−1). Resting membrane potential (Vm), recorded at various positions through the thickness of WCM strips did not differ and averaged −50 mV. Slow waves were observed in 83 % of muscles. They averaged 12 mV in amplitude, 9.4 s in duration and had a frequency of 2–4 contractions min−1. Slow waves were greatest in amplitude near the submucosal edge and decreased with distance away from this edge. Each slow wave was associated with a transient contraction. Near the myenteric edge, rapid fluctuations of Vm with a mean frequency of 18 contractions min−1 were recorded in 67 % of muscles. Spiking activity was common and was superimposed upon slow waves and rapid Vm fluctuations. In summary, slow waves were identified in the human colonic circular muscle layer which arise at or near the submucosal edge. These electrical events give rise to a 2–4 contractions min−1 contractile rhythm which is characteristic of the intact muscle layer. Thus, the nature and spatial organization of pacemaker activity in the human colon bears significant resemblance to other animal models, such as the dog and pig.

The toxicology of hydroquinone has been reviewed on a number of previous occasions. This review targets its potential for carcinogenicity and possible modes of carcinogenic action. The evaluation made by IARC (1999) of its carcinogenic risk to humans was that hydroquinone is not classifiable as to its carcinogenicity to humans (Group 3). This evaluation was based on inadequate evidence in humans and limited evidence in experimental animals. The epidemiological information comes from four cohort studies involving occupational exposures. A cohort of lithographers, some of whom had worked with hydroquinone, had an excess of malignant melanoma based on five cases, but only two of the cases had reported exposure to hydroquinone. In a study of photographic processors the number of exposed individuals was uncertain and the numbers of cases of individual cancer sites were small. In view of the statistical power limitations of these studies for individual diagnostic categories of cancers, they are not considered to be informative with regard to the carcinogenicity of hydroquinone. A cohort of workers with definite and lengthy exposure to hydroquinone, during either its manufacture or its use, had low cancer rates compared with two comparison populations; the reason for the lower than expected rates is unclear. In a motion picture film processing cohort there were significant excess malignancies of the respiratory system among workers engaged in developing, where there was exposure to hydroquinone as well as other chemicals. There was no information on tobacco smoking habits and no dose-response relationship. Hydroquinone has been shown reproducibly to induce benign neoplasms in the kidneys of male F344 rats dosed orally either by gavage (25 and 50 mg/kg body weight) or diet (0.8%). The gavage study has been evaluated in considerable detail. This evaluation showed that all renal tubule adenomas and all cases of renal tubule atypical hyperplasia occurred in areas of severe or end-stage chronic progressive nephropathy and that the neoplasms were not otherwise confined to any particular part of the kidney. It is likely that the mode of carcinogenic action of hydroquinone is exacerbation of this natural disease process. Hydroquinone is mutagenic in vitro and in vivo, having caused genotoxicity or chromosomal aberrations in rodent bone-marrow cells. At least a portion, if not all, of the chromosomal effects are caused by interference by hydroquinone or its metabolites with chromosomal segregation, probably due to interaction with mitotic spindle proteins. However, the dose routes used to demonstrate these effects in almost all of the studies in vivo were intraperitoneal or subcutaneous injection, which were considered inappropriate. There were five studies by the oral route. These included a mouse bone-marrow cell micronucleus test in which a weak, marginally positive response was obtained following a single oral dose of 80 mg/kg body weight. The remaining oral route studies all showed no significant effect. They included a mou...

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Seventy‐two chemicals were tested for their mutagenic potential in the L5178Y tk+/− mouse lymphoma cell forward mutation assay, using procedures based upon those described by Clive and Spector (Mutat Res 44:269‐278, 1975) and Clive et al. (Mutat Res 59:61‐108, 1979). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 μg/ml. The chemicals were tested at least twice. Significant responses were obtained with allyl isothiocyanate, p‐benzoquinone dioxime, benzyl acetate, 2‐biphenylamine HCl, bis(2‐chloro‐1‐methylethyl)ether, cadmium chloride, chlordane, chlorobenzene, chlorobenzilate, 2‐chloroethanol, chlorothalonil, cytarabine‐HCl, p,p′‐DDE, diazinon, 2,6‐dichloro‐p‐phenylenediamine, N,N‐diethylthiourea, diglycidylresorcinol ether, 2,4‐dimethoxy aniline‐HCl, disperse yellow 3, endosulfan, 1,2‐epoxyhexa‐decane, ethyl acrylate, ethyl benzene, ethylene thiourea, F D and C yellow Number 6, furan, heptachlor, isophorone, mercuric chloride, 4,4′‐methylenedianiline 2 HCl, methyl viologen, nickel sulfate‐6H2O, 4,4′‐oxydianiline, pentachloroethane, piperonyl butoxide, propyl gallate, quinoline, rotenone, 2,4,5,6‐tetrachloro‐4‐nitro‐anisole, 1,1,1,2‐tetrachloroethane, trichlorfon, 2,4,6‐trichlorophenol, 2,4,5‐trimetho‐xybenzaldehyde, 1,1,3‐trimethyl‐2‐thiourea, 1‐vinyl‐3‐cyclopetene dioxide, vinyl toluene, and ziram. Apart from 2‐biphenylamine‐HCl, 2‐chloroethanol, disperse yellow 3, ethylene thiourea, FD and C yellow number 6, phenol, and 1,1,2‐tetrachloroethane, rat liver S9 mix was not a requirement for these compounds. Chemicals not identified as mutagens were acid red, 11‐aminoundecanoic acid, boric acid, 5‐chloro‐o‐toluidine, coumaphos, cyclohexanone, decabromodiphenyl oxide, di(2‐ethylhexyl)adipate, ferric chloride, fluometuron, melamine, monuron, phenesterin, phthalimide, reserpine, sodium dodecyl sulfate, 4,4‐sulfonyldianiline, tetrachloroethylene, and zearalenone. The assay was incapable of providing a clear indication of whether some chemicals were mutagens; these were benzyl alcohol, 1,4‐dichlorobenzene, phenol, succinic acid‐2,2‐dimethyl hydrazide, and toluene.