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PubMed1987

The predictivity of animal bioassays and short-term genotoxicity tests for carcinogenicity and non-carcinogenicity to humans.

The successful use of surrogate tests to predict whether a chemical may be carcinogenic to humans requires that the tests be both sensitive (few false negatives) and specific (few false positives). To assess specificity, results for non-carcinogens must be compared. Although no chemicals have been definitively shown not to cause cancer in humans, we have identified 29 chemicals for which some evidence of non-carcinogenicity exists in evaluations by the International Agency for Research on Cancer. Twenty of these probable non-carcinogens have been tested for rodent carcinogenicity in animal bioassays; 19 were positive and only one was negative, indicating that the specificity of animal bioassays is low. The sensitivity of animal bioassays, however, is very high: all definite human carcinogens adequately tested were positive. Most short-term tests which measure genotoxicity or transformation also had low specificity; however, four tests gave predominantly negative results for probable human non-carcinogens as well as predominantly positive results for definite human carcinogens. These results are based on comparison of small numbers of chemicals, but do suggest the need for more investigation of the relationships of genotoxicity and rodent carcinogenicity to carcinogenicity in humans.

Animals↗
PubMed2006

Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study.

Some compounds have structural isomers of which one is apparently carcinogenic, and the other not. Because of the similarity of their chemical structures, comparisons of their effects can allow gene expression elicited in response to the basic skeletons of the isomers to be disregarded. We compared the gene expression profiles of male Fischer 344 rats administered by daily oral gavage up to 28 days using an in-house oligo microarray. 2-Acetylaminofluorene (2-AAF), 2,4-diaminotoluene (2,4-DAT), 2-nitropropane (2-NP), and 2-nitro-p-phenylenediamine (2-NpP) are hepatocarcinogenic. However, their isomers, 4-acetylaminofluorene (4-AAF), 2,6-diaminotoluene (2,6-DAT), 1-nitropropane (1-NP), and 4-nitro-o-phenylenediamine (4-NoP), are non-hepatocarcinogenic. Because of the limited carcinogenicity of 2-NpP, we attempted to perform two-parametric comparison analyses with (1) a set of 4 isomers: 2-AAF, 2,4-DAT, 2-NP, and 2-NpP as "carcinogenic", and 4-AAF, 2,6-DAT, 1-NP, and 4-NoP as "non-carcinogenic"; and (2) a set of 3 isomers: 2-AAF, 2,4-DAT, and 2-NP, as "carcinogenic", and 4-AAF, 2,6-DAT, and 1-NP as "non-carcinogenic". After ratio filtering and Welch's approximate t-test analysis, 54 and 28 genes were selected from comparisons between the sets of 3 and 4 isomers, respectively, for day 28 data. Using hierarchical clustering analysis with the 54 or 28 genes, 2-AAF, 2,4-DAT, and 2-NP clustered into a "carcinogenic" branch. 2-NpP was in the same cluster as 4-NoP and 4-AAF. This clustering corresponded to the previous finding that 2-NpP is not carcinogenic in male Fischer 344 rats, which indicates that comparing the differences in gene expression elicited by different isomers is an effective method of developing a prediction system for carcinogenicity.

Animals↗
PubMed1990

Response of the ke test to NCI/NTP-screened chemicals. I. Non-genotoxic carcinogens and genotoxic non-carcinogens.

The response of a physico-chemical carcinogen-screening test, the k(e) test, to 46 rodent carcinogens and 20 putative non-carcinogens that had been screened in long-term two-species bioassays by the National Cancer Institute/National Toxicology Program are reported. All of the chemicals screened are those that yield mutagenicity responses in the Ames Salmonella/microsome test that are either equivocal or contrary to the rodent carcinogenicity responses. The electron attachment rate constants, k(e)S, of the test chemicals in cyclohexane at 21 degrees C were measured using a pulse-conductivity technique. The k(e)S of 27 of the 46 rodent carcinogens (59%) are equal or greater than the diffusion-controlled k(e) of carbon tetrachloride, which is regarded as the boundary between a positive and negative response; the k(e)S of 8 of the 20 mutagenic non-carcinogens (40%) are less than diffusion-controlled. If the boundary between positive and negative k(e) responses is decreased to half the diffusion-controlled k(e), six additional carcinogens yield a positive ke response which increases the k(e) test sensitivity to 72% while the specificity to non-carcinogens remains at 40%. Comparison of these k(e)S with measures of the chemicals' electrophilicity that had been inferred from chemical structure indicates that k(e) provides a markedly different measure of electrophilicity and one that complements the Ames Salmonella assay. The use of the k(e) test as an analytical tool to indicate the presence of electron-attaching impurities in solvents such as benzene is discussed, as is the sensitivity of the k(e) test to rodent-liver carcinogens.

Animals↗
PubMed1992

Response of the ke test to NCI/NTP-screened chemicals. II. Genotoxic carcinogens and non-genotoxic non-carcinogens.

A physico-chemical carcinogen-screening test was used to measure the rate constants of electron attachment, kes, of 105 chemicals that had been screened in long-term rodent bioassays and short-term in vitro tests by the NCI/NTP. In the ke test, a pulse-conductivity technique is used to generate and monitor the decay of excess electrons that serve as nucleophilic surrogates for the target tissue of rodents. Of the 61 chemicals that had been found to be rodent carcinogens as well as Salmonella mutagens, 36 yield kes that are equal to or greater than the diffusion-controlled ke of carbon tetrachloride and are considered to be positive ke test responses. In contrast, 29 of the remaining 44 chemicals that are putative non-carcinogens and non-mutagens yield kes that are negative ke test responses. These results are combined with the ke responses of 46 non-mutagenic carcinogens and 20 mutagenic non-carcinogens that were reported earlier and are evaluated to determine the degree to which the measure of electron-accepting capacity that ke provides complements or overlaps the electrophilicity or DNA reactivity of chemicals that is indicated by positive mutagenicity responses in the Ames Salmonella tester strains or by positive structural alerts, S/As, of the chemicals. The combined ke test results indicate that the overall predictivity of the ke test is comparable to and complements the Ames Salmonella test and S/As in identifying rodent carcinogens. Moreover, the electrons serve as non-discriminate nucleophilic targets for both genotoxic and non-genotoxic electron-accepting molecules and appear to attach with equal efficiency to carcinogens that are active in various tissues of rodents. This property of excess electrons suggests that the predictivity of the ke test could be enhanced by combining the measured ke with an appropriate lipophilicity or pharmacokinetic parameter. A pre-chemical electron-transfer step that had been proposed to precede chemical interactions between the carcinogen and target tissue is discussed in light of recent developments in electron-donor/-acceptor chemistry and in the application of structure--activity relationships to identify carcinogens.

Animals↗
PubMed1996

Induction or suppression of SV40 amplification by genotoxic carcinogens, non-genotoxic carcinogens or tumor promoters.

Carcinogens are generally classified into two groups: genotoxic and non-genotoxic. As the final product of genotoxic and non-genotoxic carcinogens is the same, i.e., a clone of genetically altered cells, it could be possible that non-genotoxic carcinogens may yield genotoxic events as a secondary result of cell toxicity having led to mitogenesis/cellular proliferation, or that genetic alterations are induced that are normally neglected in genotoxicity tests. A genetic effect with possible relevance for the ultimate mechanism of carcinogenicity is the amplification of oncogenes. In the present experiments, amplification of SV40-virus DNA in transformed CO631-cells has been measured. In this system, two genotoxic carcinogens (positive control), two non-carcinogens (negative control), and eight non-genotoxic carcinogens have been tested. With the exception of testosterone and BVDU, all substances were tested when given alone. Testosterone and BVDU were tested in combination with either MTX or AMP in the presence or absence of S9-mix. The genotoxic carcinogens TEM and 4-NQO as well as the tumor promoters TPA, coumarin, mezerein and chrysarobin were able to induce SV40 amplification when given alone. The same was for acetamide and thioacetamide. The non-carcinogens acetone and dimethylformamide were ineffective. In case of testosterone, a co-amplification effect was seen in the absence of S9-mix, and an anti-amplification effect in presence of S9-mix. The anti-recombinogen BVDU reduced the SV40 amplification effect of AMP in experiments without addition of S9-mix. In the presence of activating S9-mix, this substance was effective at lower concentrations than without S9-mix, and showed an enhanced anti-amplification effect. Similar effects of testosterone and BVDU had been observed before in respect to stimulation or suppression of recombination. These results can be used as supportive evidence for the assumption that gene amplification is mechanistically related to recombination.

Acetamides↗
PubMed1997

Influence of carcinogen binding by lactic acid-producing bacteria on tissue distribution and in vivo mutagenicity of dietary carcinogens.

The aims of this investigation were to determine whether viable cultures of lactic acid-producing organisms (LAB) can bind dietary carcinogens and to assess the consequences of binding for the absorption from the gut, distribution in the body and in vivo genotoxicity of ingested carcinogens. The carcinogens used in this study were ones known to be present in the human diet, namely benzo[a]pyrene (B(a)P, aflatoxin B1 (AFB1) and the cooked food carcinogens 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 5-phenyl-2-amino-1-methylimidazo [4,5-f]pyridine (PhIP) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). They represent a range of structural types so that the specificity of any binding effects could be addressed. Of the carcinogens tested, B(a)P and Trp-P-2 were bound most effectively by the two LAB strains Bifidobacterium longum and Lactobacillus acidophilus. AFB1 was poorly bound, while MeIQx, MeIQ, PhIP and IQ were bound to an intermediate degree. The extent of the binding of the heterocyclic amine carcinogens was dependent on the pH conditions during incubation and this effect was more apparent with B. longum than with L. acidophilus. Using the host-mediated assay (HMA), an in vivo bacterial mutation assay, it was demonstrated that the administration of bacterial cell suspensions of B. longum and L. acidophilus did not lead to a reduction in induced mutagenicity by MeIQ, MeIQx or Trp-P-2, detectable in the liver of treated mice compared with controls. The lack of a protective effect could not be attributed to a short period of contact between bacterial cells and mutagens, since similar results were obtained after preincubating bacteria and mutagens together at pH 5 for 50-60 min, to maximize the binding, before gavaging the mice. Lack of activity of B(a)P in the HMA prevented the determination of the effect of LAB on genotoxicity of the polycyclic aromatic hydrocarbon. However, it is clear from the radiolabel distribution study that the amount of the carcinogen entering the blood was not significantly reduced by B. longum administration. In addition, the amount of radiolabelled B(a)P that reached the target organs (liver, lungs and heart) was also not affected by the LAB administration. A similar lack of inhibitory effect of B. longum on blood concentration and accumulation in the liver of Trp-P-2 was apparent. The results of the present study suggest that although LAB may bind carcinogens in vitro, this does not lead to major changes in absorption and distribution of carcinogens in the body, or in their genotoxic activity in the liver.

Animals↗
PubMed1978

[Nuclear DNA synthesis rate and labelling index: effects of carcinogenic and non-carcinogenic chemicals on its behaviour in the organism of growing CBA-mice. The thymidine-incorporation-screening-system (TSS) (author's transl)].

During the last few decades there has been an extraordinary accumulation of man-made chemicals in the human environment. There is a growing consensus in oncology that a large proportion of human cancers are environmental in origin by exposure of man to such carcinogenic chemicals. These chemicals in the majority of all cases have not been tested to prove their carcinogenicity. Testing of new chemical compounds is needful prior to their introduction into commerce, foods, agriculture or the working places to prevent human cancer. To test such a large number of possibly carcinogenic chemicals, economical and rapidly practicable bioassays are necessary. In the following we compare some well known bioassays with our autoradiographic thymidine-incorporation-screening-system and other assays based on biochemical quantification of DNA synthesis as parameter for identification of carcinogenic substances. The partial inhibition of the whole DNA synthesis in a proliferating cell population after treatment with toxic and carcinogenic chemicals is an early common response especially in hepatectomized animal, livers caused by the effects of those substances. However, by quantitative evaluation of the nuclear DNA synthesis rate as a basic parameter using autoradiographs of kidney and liver of juvenile growing CBA-mice, it is possible to differentiate carcinogenic from non-carcinogenic chemicals by means of silver grain counting after 3H-TdR incorporation. Contrarily the "whole DNA synthesis" expressed by the percentual 3H-labelling index of kidney and liver did not permit such a differentiation in our experimental arrangement. We could demonstrate that carcinogenic compounds of different chemical classes partially inhibit the nuclear DNA synthesis rate significantly over a time period longer than 24 hours. The tested non-carcinogenic compounds did not show this suppressive effect on the nuclear DNA synthesis rate.

Animals↗
PubMed1984

Target polypeptide of a carcinogen is associated with normal mitosis and carcinogen-induced hyperplasias in adult hepatocytes.

Normal rat liver cytosol was found previously to contain a 14,000-dalton polypeptide that is the principal target of the carcinogen N-2-fluorenylacetamide (2-acetyl-aminofluorene) early during hepatocarcinogenesis. By using antiserum that identifies the 14,000-dalton polypeptide in liver cytosol, an immunologically related 17,500-dalton polypeptide was shown to be present in isolated normal liver nuclei, tightly bound to chromatin. We report here that the 14,000-dalton polypeptide is associated with cell multiplication in normal adult hepatocytes. Of 150 hepatocytes in five stages of mitosis, all invariably displayed a greatly increased concentration of the 14,000-dalton polypeptide in cytoplasm, compared to hepatocytes in interphase, by immunostaining with peroxidase-antiperoxidase complex. In contrast, mitosis did not appear to affect the level of the 17,500-dalton polypeptide in nuclei. A small population of high-polyploid hepatocytes with large nuclei had elevated intensities of cytoplasmic immunostain that approached that in mitotic cells. The increased level of discernible 14,000-dalton polypeptide target of the carcinogen in cytoplasm is a marker of the rare mitotic hepatocytes in normal adult rat liver. Ingestion of the liver carcinogen N-2-fluorenylacetamide for 5 wk or an azocarcinogen, 3'-methyl-4-dimethylaminoazobenzene, for 4 wk brought about early foci of hyperplastic hepatocytes in which there was a great overload of detectable 14,000-dalton target polypeptide in their cytoplasm and a near absence of the 17,500-dalton polypeptide in most nuclei. In contrast, the cytoplasm and nuclei in surrounding morphologically nontransformed hepatocytes of livers of the carcinogen-fed rats immunostained to a much smaller degree than in normal adult hepatocytes. Removal of the azo-dye carcinogen for 4 wk resulted in the disappearance of most hyperplastic foci. A few foci did persist and had similar apparent abnormal levels of the two polypeptides. The high concentration of discernible 14,000-dalton target polypeptide in the cytoplasm of hepatocytes in the hyperplastic foci correlates with their known proliferation, whereas the low cytoplasmic level in the surrounding hepatocytes is consistent with the known inhibition of their mitosis by these carcinogens. The collected evidence appears to joint together a chemical carcinogen, a cytoplasmic principal target polypeptide, a chromatin-bound polypeptide, mitosis in normal adult hepatocytes, early and persistent hyperplastic foci caused by carcinogens, and the inhibition of mitosis by carcinogens in surrounding parenchyma in preneoplastic livers.

2-Acetylaminofluorene↗
PubMed1990

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper 1/2. A multi-factor ranking scheme for comparing the carcinogenic activity of chemicals.

A scheme for ranking the quantitative activity of chemical carcinogens is described. This activity scheme uses as its base, dose potency measured as TD50, the chronic dose rate that actuarially halves the adjusted percentage of tumor-free animals at the end of the study (Gold et al., Environ. Health Perspect., 67, 161-200, 1986). The TD50 is converted into an inverse log scale, a decile scale, and then adjusted by weighting factors that describe other parameters of carcinogenic activity. These factors include positive or negative weightings for: the induction of tumors at tissues or organs associated with high historical control tumor incidences; the induction of tumors at multiple sites; the induction of tumors in both sexes of the species; and the induction of tumors in more than one species. These factors were chosen as they represented qualitative descriptions of the general specificity or non-specificity of chemicals with regard to the activity in rodents and have some bearing on the potential activity of chemicals in humans. In order to construct a measure to express the inactivity of chemicals towards the induction of cancer, a measure analogous to the TD50 has been developed: the highest average daily dose or HADD. The HADD is the highest average daily dose in mg chemical/kg body weight administered in a chronic cancer study and that did not induce a statistical increase in tumors. HADD values were similarly converted to log decile units and adjusted by weighting factors according to lack of activity in both sexes of a species, and the lack of activity in more than one species. In order to explore the use of this multi-factor activity scheme for both carcinogens and non-carcinogens, a group of 142 chemicals was selected that had been tested according to an oral dosing protocol in two sexes of two species of rodents and whose data was peer-reviewed and available for this analysis. This data came from the National Toxicology Program/National Cancer Institute Bioassay Technical Reports. Three activity ranking schemes were developed: the Carcinogen Activity-F344 Rat, an activity scheme based on cancer data obtained with the F344 rat; the Carcinogen Activity-B6C3F1 Mouse, an activity scheme based on cancer data obtained with the B6C3F1 mouse, and the Carcinogen Activity-Combined, an activity scheme based on selecting data from both the F344 rat and the B6C3F1 mouse. This selection was based on the most sensitive rodent responding to the carcinogenic activity of active chemicals and the least sensitive rodent responding to the toxic effects of inactive chemicals.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1996

Reappraisal of eight representative carcinogenic and non-carcinogenic compounds in a new medium-term rat liver bioassay using D-galactosamine.

The carcinogenic potential of eight different compounds was assayed in a new medium-term carcinogenicity bioassay using D-galactosamine (DGA) as a non-surgical method to induce regeneration in place of partial hepatectomy (PH). Male rats were initially given a single i.p. injection (200 mg/kg) of diethylnitrosamine (DEN) and after 2 weeks on basal diet, received two i.p. injections of DGA (300 mg/kg) at the end of weeks 2 and 5. They were treated with one of the test compounds aflatoxin B1, benzo[a]pyrene, diethylstilbestrol, urethane, sodium saccharin, bucetin, D-mannitol and sodium chloride in the diet or basal diet alone for weeks 3-8. Carcinogenic potential was assessed by comparing the numbers and areas per cm2 of glutathione S-transferase placental form-positive (GST-P+) foci in the livers of treated animals with those of the control animals given DEN/DGA alone. Positive estimations of carcinogenicity were obtained for the hepatocarcinogens aflatoxin B1, diethylstilbestrol or urethane, and for the non-liver carcinogen benzo[a]pyrene. Negative values were shown in rats treated with the non-carcinogens, D-mannitol and sodium chloride. The two other non-liver carcinogens sodium saccharin and bucetin, also did not exert positive effects in the system. The present data are consistent with findings in previous medium-term bioassays using PH. Our results thus confirm that the present bioassay protocol with repeated administration of DGA instead of PH may offer a new and sensitive non-invasive method to screen large numbers of environmental carcinogens.

Animals↗
PubMed1996

Anomalous nonidentity between Salmonella genotoxicants and rodent carcinogens: nongenotoxic carcinogens and genotoxic noncarcinogens.

According to current data, the capacity to cause nonprogrammed or unscheduled cell proliferation in target tissues, a common characteristic of chemical carcinogens, may play a more important role in the development of tumors than does genotoxicity. This paper provides strong support for the validity of this conclusion. Ames-negative nongenotoxicants may be considered to be carcinogenic primarily because of their ability to induce cell proliferation in animal tissues and organs. In addition, such nongenotoxic carcinogens may also provide latent and modest DNA (equivocal) modifications that never lead to Ames-positive events. Conversely, noncarcinogenesis by Ames-positive agents is likely to be linked to a lack of stimulation of cell division. Nongenotoxic and genotoxic carcinogens rely on both cell proliferation and equivocal DNA modification for their full carcinogenicity. Such equivocal DNA modifications do not appear to be formed by tumor promoters. The role of cell proliferation may provide a favorable milieu for the occurrence of genetic instability, give rise to selective "apoptosis-resistant abnormal cells," and then affect clonal expansion of these cells. Therefore, understanding the influence of nongenotoxic and genotoxic carcinogens on cell proliferation capability is a key point in determining the mechanisms of chemical carcinogenesis. Considering the contradictory and common features of genotoxicants and carcinogens, early detection of nonprogrammed cell proliferation is the most effective approach to predict human and rodent carcinogenicity.

Animals↗
PubMed2006

Effect of some carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons on gap junction intercellular communication in hepatoma cell cultures.

One of the systems that regulate tissue homeostasis is gap junction intercellular communication (GJIC). It is accepted that the down-regulation of GJIC is linked to the tumor-promoting properties of carcinogens. In this study, the effect of some carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons (PAH) on GJIC was investigated. It was found that in hepatoma cell culture (Hep G2) carcinogenic PAH inhibited GJIC after 24 h exposure by 75-100% depending on the PAH structure. The inhibition effect on GJIC is reversible because removing the PAH by changing of culture medium restores the GJIC. The non-carcinogenic PAH do not significantly influence GJIC. alpha-Naphthoflavone, an inhibitor of PAH metabolism, has no effect on inhibition of GJIC by carcinogenic PAH. 2,3,7,8-Tetrachloro-p-dibenzodioxin, an aryl hydrocarbon (Ah) receptor ligand, inhibits GJIC by about 50% only after 48 h exposure. To clarify the role of formation of PAH metabolites and interaction with Ah receptor on inhibition of GJIC, we determined the effect of benzo/a/pyrene on hepatoma G27 cells in which neither mRNA of CYP1A1 nor Ah receptor was determined. As in Hep G2 cells, benzo/a/pyrene, unlike non-carcinogenic benzo/e/pyrene, inhibits GJIC. We conclude that in the studied hepatoma cells carcinogenic PAH inhibit GJIC directly (that is, not via their metabolites) and this effect is not associated with Ah receptor interaction.

Animals↗
PubMed1999

Carcinogens in the diet vs. overnutrition. Individual dietary habits, malnutrition, and genetic susceptibility modify carcinogenic potency and cancer risk.

Chemical carcinogens in the diet cannot explain the cancer incidence attributed by epidemiologists to dietary factors when the calculation is based on average exposure levels and conservative estimates of carcinogenic potencies. In a previous review, the discrepancy was explained primarily by overnutrition to which a carcinogenic potency was assigned from dietary restriction experiments and the associated reduction in spontaneous tumor incidence (W.K. Lutz and J. Schlatter, Chemical carcinogens and overnutrition in diet-related cancer, Carcinogenesis 13 [1992] 2211-2216). Here, additional aspects are introduced. They focus on using individual rather than averaged data, both for exposure and susceptibility. First, under conditions of a sublinear (convex) dose-response, the cancer incidence obtained by using an average exposure level is lower than if individual exposure levels associated with particular dietary habits are taken into account. Second, carcinogenic factors, including those unrelated to the diet (e.g., smoking), can act synergistically. Third, the potency of dietary carcinogens is increased under conditions of malnutrition in the sense of a deficiency of protective factors, such as those available with fruits, vegetables, and fibers. Quantitatively, this aspect may be particularly important because it simultaneously increases the efficacy of a multitude of carcinogens. It is concluded that chemical carcinogens could be as important as overnutrition for diet-related cancer.

Alcohol Drinking↗
PubMed1997

T25: a simplified carcinogenic potency index: description of the system and study of correlations between carcinogenic potency and species/site specificity and mutagenicity.

A simplified carcinogenic potency index, the T25, is proposed as a practical method for the inclusion of potency considerations in carcinogen classification systems. The T25 is the chronic daily dose in mg per kg bodyweight which will give 25% of the animals tumours at a specific tissue site, after correction for spontaneous incidence, within the standard life span of that species. Calculated T25 values of a set of 113 US National Cancer Institute/National Toxicology Program (NC/NTP) carcinogens showed excellent correlation (correlation coefficient 0.96, P < 0.0001) with the carcinogenic potency index TD50 of Peto et al. (1984). The mean of T25 values for 51 transspecies, multiple common site NCI/NTP carcinogens were 10-fold lower than those for 62 NCI/NTP single species, single site carcinogens. For these 113 carcinogens, the mean T25 values were approximately 3-fold lower for agents that were also mutagenic in Salmonella compared to the non-mutagenic agents.

Abdominal Neoplasms↗
PubMed1999

Carcinogenic chemical-response "fingerprint" for male F344 rats exposed to a series of 195 chemicals: implications for predicting carcinogens with transgenic models.

Transgenic model systems have recently been advocated as replacements for traditional methods of testing chemicals for carcinogenicity in rodents. To shed light on the diversity of responses induced by chemicals in natural whole animal systems, a type of "fingerprint" is devised and, in turn, applied to describe the results of testing approximately 200 chemicals in male F344 rats. Such focus helps develop an appreciation of the complexity involved in the chemical carcinogenic response. When we ask transgenic systems to serve as replacements for natural whole animals, for predicting the risk of chemically induced cancer, we are asking them somehow to reflect or express this complexity so that the effects of exposure in humans can be realistically appraised. For the fingerprint, a graphic data display is used to represent the different tissues and organs that show statistically significant, chemically related tumor increases. Chemicals vary extensively according to the particular sites and the array of sites that display a carcinogenic response; but any given site may also show a carcinogenic response to a variety of different chemicals. The data suggest that a large number of different genetic factors may underlie the determination of the chemical carcinogenic response. This apparent genotypic variability and complexity in phenotypic expression would seem to make it quite difficult, if not impossible, to decide on the specific performance requirements of transgenic systems for detecting carcinogens. Unless this and other obstacles can be overcome, the transgenic approach to identifying carcinogenic chemicals for regulatory purposes may best be abandoned. Published 1999 Wiley-Liss, Inc.

Animals↗