Division of Intramural Research; National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
Received August 3, 1999; accepted January 4, 2000
Arsenic has long been known to cause cancer in humans (Hutchinson, 1987, 1988
), and has been correlated convincingly with cancers of the skin, lung, liver, kidney, and urinary bladder (IARC, 1987
; NTP, 2000
). Paradoxically, we now know that arsenic has been shown to be "anticarcinogenic" as well, and of potential benefit in the treatment of acute promyelocytic leukemia (Zhu et al., 1999
). Whereas this is a major cancer chemotherapeutic advance, we believe use of arsenicals in human medicine must be tempered by toxicological realities (Huang et al., 1998
; Huff et al., 1999
). Nonetheless, most if not all cancer chemotherapeutic agents are carcinogenic to animals, and cause eventual second primaries in humans.
In summarizing the informative and valued proceedings from a recent symposium on arsenic, Goering et al. (1999) stated that "animal carcinogenicity data for arsenic is considered either negative or equivocal." These authors make a more discerning statement two paragraphs later: "Animal bioassays are considered either flawed or incomplete for establishing carcinogenicity of arsenic in rodents." They also contend that "the International Agency for Research on Cancer (IARC) has determined that arsenic is the only agent to be a definitive human carcinogen in the face of `inadequate' evidence of carcinogenic potential in animals."
In fact, none of these statements is fully correct; the second quoted sentence above comes close. In 1987 IARC evaluated arsenic and arsenic compounds and concluded "there is limited evidence of carcinogenicity in experimental animals," meaning there are tumor responses in some studies on arsenic carcinogenicity in animals but due to certain deficiencies (too few animals, low doses, short duration, no controls, arsenic mixtures) the findings were not considered sufficient evidence of carcinogenicity in animals. In these assorted and seemingly numerous studies, various forms of inorganic arsenic were associated with tumors of the lung, respiratory tract, and stomach (IARC, 1980, 1987
). Moreover, as we have stated previously (Huff et al., 1998a
,b
), arsenic trioxide and other inorganic (and until now organic) arsenicals have in reality never been tested adequately for carcinogenesis, and never by the inhalation route. Thus, to state that arsenic has not been shown to cause cancer in laboratory animals is patently premature (Chan and Huff, 1997
). Unfortunately, a common and perpetuated incorrect statement is often made that arsenic is carcinogenic to humans and not to experimental animals. Bioassays should be done, in particular with arsenic trioxide, to satisfy this frequently but wrongly opined discrepancy.
As history often repeats, this reminds some of us of when benzene was also heralded as being carcinogenic to humans but not to animals, and the "lack" of carcinogenicity in animals for both arsenic and benzene was used to discount the relevancy of bioassay testing results for predicting human cancer risks. It is now clear that, after adequate testing of benzene in animals, the results have been overwhelmingly positive for carcinogenicity (Huff et al., 1989; Maltoni et al., 1989
). We believe the same will occur if inorganic arsenic is tested properly in laboratory animals.
In addition to arsenic, and contrary to the quoted comment by Goering et al. (1999), other IARC Group-1 human carcinogens have less than sufficient evidence of carcinogenicity in animals, largely because only one study has been reported, and in some cases there is no evidence at all because no bioassays have been done. These substances are listed in Table 1. For some of these there may be more recent experimental data that we are either unaware or have been unable to locate. Despite this collective observation, correlations between bioassays and epidemiology findings are excellent (Huff, 1994
, 1998
, 1999a
; Tomatis et al., 1989
; Wilbourn et al., 1986
).
|
|
Thus, by no means should arsenic be singled out as being uniquely carcinogenic in humans and not convincingly in experimental animals. Indeed, any of the human carcinogens either not tested adequately or not studied for carcinogenicity at all would be considered in this category. Partial listings of these are given (Tables 1 and 2). Further in fact, there are no human carcinogens that could be or have been tested in animals that have been shown unequivocally negative. Quite the contrary: all have been shown to cause cancer in laboratory animals (Huff, 1994
, 1998
; Huff and Rall, 1992
; Tomatis 1989; Wilbourn et al., 1986
).
In addition, in 1987, IARC stated that "No adequate data on the carcinogenicity of organic arsenicals were available to the Working Group." Since IARC's last review, bioassays have been reported that show that dimethylarsinic acid (DMAA; cacodylic acid; and a metabolite of arsenics), typical of the organic arsenicals, induced cancer of the urinary bladder in rodents, a site concordant with that seen in humans, and DMAA also promoted tumors in several other organs (van Gemert and Eldan, 1998; Wei et al., 1999
; Wanibuchi et al., 1999
). This indicates that humans and rodents seem to possess a similar tendency to develop these shared-site tumors when exposed to organic and inorganic arsenicals.
DMAA, as well as monomethylarsinic acid (MMAA), is a major form of arsenic in the environment, resulting largely from its use as a general herbicide or pesticide. Importantly, DMAA, along with MMAA, is the major methylated metabolite of ingested organic or inorganic arsenics in most mammals, including humans (Goering et al., 1999; Vahter, 1994
). DMAA is eliminated via the kidney, and excreted in the urine. Thus, taken together, results from laboratory studies using DMAA should be considered relevant to the carcinogenic risk of arsenics and arsenicals to humans.
In laboratory studies, DMAA acts as a tumor promoter in addition to being a complete carcinogen. DMAA (i) promoted urinary bladder tumors in Fischer and NBR rats using N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as the initiator (Li et al., 1998; Wanibuchi et al., 1996
), (ii) promoted lung tumors in 4NQO-initiated male ddY mice (Yamanaka et al., 1996
), and (iii) promoted liver tumors in rats initiated with diethylnitrosamine (Johansen et al., 1984
). In a multiorgan assay, DMAA promoted tumors of the urinary bladder as well as of the kidney, liver, and thyroid glands in rats (Yamamoto et al., 1995
). DMAA increased the numbers and areas of glutathione S-transferase placental form-positive foci in the liver of rats initiated with diethylnitrosamine, an assay system confirmed to identify liver carcinogens (Yamamoto et al., 1997
). Clearly then, DMAA promotes multiple-site tumors in a variety of organs in multiple species, and causes DNA damage and chromosomal aberrations.
Recent bioassay reports show unequivocally that DMAA administered in feed or drinking water for two years caused urothelial tumors in Fischer 344 rats (van Gemert and Eldan, 1998; Wei et al., 1999
; Wanibuchi et al., 1999
), and fibrosarcomas in B6C3F1 mice. As reported in an unpublished memorandum (Carcinogenicity peer review of cadocyclic acid, by S. Malish and E. Rinde, Office of Prevention, Pesticides, and Toxic Substances, U.S. EPA, July, 1994), mice were fed diets containing 0, 8, 40, 200, and 500 ppm DMAA for 104 weeks; F344 rats were given 0, 2, 10, 40, and 100 ppm DMAA. (This report on the 1989 rat study and the 1990 mouse study was just brought to our attention.) In female mice, multiple organ fibrosarcomas were increased at the 500 ppm exposure (2/56 controls vs. 0/55, 1/56, 1/56, 6/56, respectively); increases in fibrosarcomas were observed also in male mice: 0/56 controls vs. 0/56, 2/56, 4/56, 2/56, respectively.
DMAA induced rarely occurring transitional cell papillomas and carcinomas of the urinary bladder of rats, most strikingly for females: 0/59 controls vs. 0/59, 0/57, 0/56, 10/58, respectively, or 17%; males: 0/60 controls vs. 1/59, 1/59, 1/57, 2/55, although male rats showed tumors at lower doses (EPA, 1994). Similar non-neoplastic lesions of the urinary bladder (e.g., vacuolar degeneration) were observed in both sexes of both species exposed to DMAA, whereas hyperplasias were increased only in rats. The EPA (1994) indicated that, for both sexes of rats and for female mice, the dietary exposure concentrations of DMAA could have been higher.
As reported in an abstract, DMAA, at an exposure level of 100 ppm in feed, induced both urinary bladder hyperplasia and transitional cell tumors (papillomas and carcinomas) in rats of both sexes, apparently more frequently among females; no tumor incidence data are given (van Gemert and Eldan, 1998). Evidently, no neoplastic effects were observed at the next-lower exposure concentration of 40 ppm. Also reported in this abstract, a study in B6C3F1 mice at exposures of 0, 8, 40, 200, and 500 ppm DMAA in the diet for two years showed no evidence of carcinogenic activity. (Both rat and mouse studies were reported as an abstract, with incomplete information). Note: Arnold et al. (1999), apparently reporting on these same data, stated that "an increased incidence of bladder tumors and hyperplastic lesions in F344 rats when [DMAA was] fed in the diet in a 2-year bioassay, at doses of 40 or 100 ppm (van Gemert and Eldan, 1998
), but no significant incidences of bladder lesions were observed at doses of 2 or 10 ppm" (no data were given). However, in the referenced abstract to this finding, van Gemert and Eldan (1998) indicate tumors only at the "high dose" (100 ppm), where likewise no incidence rates are given.
It should be noted that the remarkable similarity between the EPA report (1994) and the abstract by van Gemert and Eldan (1998), especially for rats, causes us to wonder if these findings are from the same studies. Only the EPA (1994) gives incidence data. Hence, because of the sketchiness of the abstract, differences in the evaluations of the mouse data (fibrosarcomas), and indications of lower-dose carcinogenicity in rats by Arnold et al. (1999), ostensibly of the van Gemert and Eldan (1998) data, we must await more detailed publication to untangle this issue.
In another abstract, Ng et al. (1998) reported a 26-month study in C57Bl/6J and metallothionein knockout female mice given sodium arsenate in drinking water (500 ppm). Control groups of mice were given normal tap water. The authors stated that "preliminary findings indicate that 37/90 (41.1%) C57Bl/6J and 37/140 (26.4%) MT mice had one or more tumors." Increases were reported for a plethora of sites: gastrointestinal tract, lung, liver, spleen, bone, skin, reproductive system, and eye. Few details are given, and surprisingly, "no tumors were observed in the control groups." The significantly important finding in this study is the induction of cancers from inorganic arsenic, which certainly adds to the accumulating evidence (IARC, 1987; Chan and Huff, 1997
; Huff et al., 1998a
,b
). The contrast in tumor responses between the B6C3F1 (EPA, 1994; van Gemert and Eldan, 1998
) and C57Bl/6J (Ng et al., 1998
) mice is striking, confusing, and unanticipated. Of course, one must await publication of the full results of these studies before drawing firm conclusions.
Other bioassays on DMAA showed confirmatory carcinogenic activity for the urinary bladder. Wanibuchi et al. (1999) exposed male Fischer 344 rats to DMAA in both a two-stage rat urinary bladder model, using BBN, as well as a two-year bioassay. In the promotion model, DMAA, in addition to monomethylarsonic acid (MMAA) and trimethylarsine oxide (TMAO), promoted tumors of the urinary bladder, whereas arsenobetaine (AsBe) and sodium arsenite did not. In the two-year study (Wei et al., 1999), DMAA in drinking water induced papillomas and carcinomas of the urinary bladder in 39% of animals exposed to 200 ppm DMAA (12/31; 2 papillomas, 12 carcinomas, with 2 animals each having one benign and one malignant tumor), in 26% of rats exposed to 50 ppm (8/31; 2 papillomas, 6 carcinomas), and in none of those exposed to 12.5 ppm or in any controls.
Thus, the three available long-term studies clearly demonstrate that DMAA is carcinogenic for the urinary bladder in rats (EPA, 1994, unpublished report; Wanibuchi et al., 1999; van Gemert and Eldan, 1998; Wei et al., 1999), for multiple organ fibrosarcomas in mice (EPA, 1994, unpublished report), and for several tumor sites in mice exposed to sodium arsenate (Ng et al., 1998). Perhaps these findings can be used to dismiss or at least question the notion that a useful animal model of arsenic carcinogenesis does not exist.
Interestingly, while both studies used Fischer rats and the same duration of exposure, one indicated females were more "sensitive" and found tumors of the urinary bladder only at the 100 ppm exposure level and none at 40 or 0 ppm (van Gemert and Eldan, 1998); in a latter report (without numerical data given), the 40 ppm group was found to have an increase in tumors of the urinary bladder (Arnold et al., 1999
). The other bioassay used male rats only and induced tumors at both 50 and 200 ppm (Wanibuchi et al., 1999
; Wei et al., 1999
). If indeed female rats are more responsive than males one would have expected tumors to have occurred in the 40-ppm group, given that the "less" sensitive males exhibited carcinogenicity at 50 ppm (not too different from 40 ppm), yet not at 12.5 ppm. Thus, one must assume from the second study that exposures lower than 50 ppm will be carcinogenic, especially if larger group sizes of animals are used. One also wonders if more tumors would be seen using durations longer than 24 months, especially since these tumors are typically late appearing and metals often induce late-stage carcinogenesis. Further, the second study exposed animals via drinking water, more consistent with human exposures, while the former added DMAA to the feed.
In none of these long-term studies are there adequate details on the extent of pathology; for example, one might be led to assume only urinary bladders were examined histopathologically. Wei et al. (1999) indicate in good detail how urinary bladders were processed and evaluated. Moreover, the multi-organ tumor promotional activity of DMAA may have misled us to operationally consider this chemical as a "promoter". Now that we know DMAA clearly causes DNA damage, "promotes" five organ site tumors, and induces tumors of the urinary bladder, we are surprised that DMAA does not induce other organ-specific carcinogenic activity as well. Perhaps this lack of other carcinogenic effects in rats might reflect limited pathology (note: even though no details were given regarding pathology, numbers of organs examined histopathologically, and so on, we strongly suspect that complete pathology was done, but this can not be stated with any certainty). This is in some contrast to the abstracted data reported by Ng et al. (1998), whereby multiple organs were affected in mice given sodium arsenate in drinking water, yet no pathology details are given. Here again the full and peer-reviewed data are needed.
Regarding "mechanism," Arnold et al. (1999; reported previously as an abstract by Cohen et al., 1999) opined that DMAA induces tumors by a "nongenotoxic" mechanism, because "current evidence indicates that DMAA is not genotoxic," and they reported that urothelial toxicity and hyperplasia of the bladder were reversible when exposure was withdrawn. These authors promote a "non-DNA reactive mechanism for DMA rat bladder carcinogenicity related to urothelial toxicity and regeneration." These authors conclude from their 10-week study that "findings strongly support a[n] ...increased cell proliferation mechanism for the carcinogenicity of DMA in rats." This "mechanism" of carcinogenicity has of course been challenged (Weinstein, 1991, 1992
; Huff, 1992
, 1995
, Farber, 1995
). It would seem "that theories based on mechanistic arguments, however attractive, must give way to substantive empirical evidence" (Stayner et al., 1997
). Whether a 10-week study, with limited time point measurements, can allow this mechanistic enunciation remains to be verified.
Lack of genotoxicity is somewhat unusual for bladder carcinogens, because most chemicals studied and evaluated by the National Toxicology Program that did cause tumors of the urinary bladder are indeed genotoxic: 15 of 18, out of 500 chemicals overall (Huff, 1999b). Perhaps other databases might have different proportions of genotoxic to nongenotoxic urinary bladder carcinogens. Nonetheless, evidence exists that DMAA induces DNA single-strand breaks in human alveolar epithelial type II cells in culture (Yamanaka et al., 1997
) and in lung cells in male ICR mice (Yamanaka et al., 1989
). DMAA certainly appears to be clastogenic and genotoxic (ATSDR, 1999
; Wei et al., 1999
). Mechanistically, of course, arsenic affects DNA repair and methylation, and causes increased radical formation and activation of the proto-oncogene c-myc (Abernathy et al., 1999
). Goering et al. (1999) suggest, as potential modes of arsenic carcinogenesis, chromosome abnormalities, altered DNA repair, altered DNA methylation, oxidative stress, and modification of cell proliferation. Regarding skin carcinogenesis using a transgenic mouse model (TgAC), other mechanisms have been proposed such as that arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors (Germolec et al., 1997
, 1998
). These latter effects on the skin were seen only in combination with TPA application, and the authors suggested that arsenic acts as a "co-promoter" or "enhancer" of skin tumors. Most likely combinations of these will prove more mechanistically responsible for arsenic carcinogenesis than any one alone. Regardless of mechanism, organic arsenic is carcinogenic to animals.
Sodium arsenite and arsenate induced morphological transformation of Syrian hamster embryo cells in a dose-dependent manner, providing another possible mechanism by which arsenic and arsenical compounds exert carcinogenic activity (Barrett et al., 1989). Cell transformation and cytogenetic effects, including endoreduplication, gene amplification, chromosome aberrations, and sister chromatid exchanges were induced with similar dose responses. Thus, these findings clearly support the conclusion that arsenic is "genotoxic."
Overall, while the collective evidence of carcinogenicity on inorganic arsenic appears quite close to being considered sufficient evidence, in experimental animals (Chan and Huff, 1997; IARC, 1980
, 1987
), an adequate and definitive long-term experiment on arsenic (and in particular arsenic trioxide) has not yet been done. Rather than state that there are no animal models to study the carcinogenicity of arsenic (e.g., Goering et al., 1999), we believe a bioassay should be accomplished in rodents to resolve the debate whether arsenic is a human carcinogen that might not cause cancer in laboratory animals. Of course, we now know that a major metabolite of arsenic acid (i.e., DMAA) is unequivocally carcinogenic to animals; we would be bewildered if inorganic arsenic, in a properly designed bioassay, turned out to not be carcinogenic to laboratory animals.
Interestingly, one existing paradox is that several governmental agencies have been less than supportive of doing a modern and adequate carcinogenesis bioassay on arsenic (NTP, 1994). Apparently their continuing reluctance stems from the certainty that arsenic is carcinogenic to humans and thus, in their opinion, little would be gained by doing a carcinogenesis bioassay. The nomination of arsenic trioxide for carcinogenicity testing has been overruled because of an alleged "lack of an appropriate animal model for human carcinogenicity" (NTP, 1999
). Their rationale is certainly imperfect, given the continuing debate surrounding this issue, and the professed lack of concordance between humans and animals has been used disingenuously to discredit bioassay results in general. Further, one needs to better think what is meant by "an appropriate model for human carcinogenicity." Notwithstanding, a long-term carcinogenesis bioassay of arsenic should be done rather than continuing to opine about an enigma or a paradox.
For DMAA, this "arsenic enigma" obviously is no longer the situation. Further, the argument that inorganic arsenic is a multiorgan carcinogen in humans, which is not or will not be carcinogenic in animals because of differences between humans and rodents in methylation-detoxification capabilities, has yet to be proven. When tested properly, DMAA certainly disproves the notion that arsenicals are not or will not be carcinogenic in animals. Additionally, we must clearly reconsider the long-held dogma that methylation of arsenics represents a "detoxification" pathway (Brown et al., 1997). Probably DMAA is the ultimate carcinogen of arsenic. Moreover, arsenic is clastogenic in both humans and animals (ATSDR, 1999
), and mechanistically, arsenic appears to be a late-stage carcinogen (Lee et al., 1985
, 1988
).
Perhaps those doing risk evaluations need to be more aware of this "toxication" mechanism when establishing arsenic exposure standards, given that methylation likely activates the "procarcinogen" arsenic to the active methylated carcinogen. Thus, individuals who methylate arsenic more efficiently and at lower doses would be presumably at greater risk; this would further indicate that the dose-response curve would doubtless be supralinear. This appears to be directly opposed to the current risk strategies for arsenic, and moreover, certainly anathema to good occupational and environmental health practices.
In summary, DMAA is a genotoxic, multi-site promoter of carcinogenesis as well as a complete carcinogen in rodents. Significantly, arsenical-induced tumors in humans and those in animals show common sites for tumors of the urinary bladder, kidney, lung, and liver. However, arsenic trioxide has not been studied adequately for carcinogenesis in animals, and it should be tested for carcinogenic potential to allay the debate about human-animal carcinogenesis concordance. Nonetheless, mechanistically we must assume that inorganic arsenics (e.g., arsenic trioxide) would be carcinogenic in mammals as they are metabolized to MMAA and DMAA, both being promoters of carcinogenesis and the latter being a complete carcinogen. Additionally we are not aware if MMAA has been studied in a long-term bioassay; perhaps it too should be tested. Finally, we tend to agree with Goering et al. (1999) that "the unsettling possibility exists that humans may be more sensitive than experimental animals to cancers induced by this ubiquitous metalloid (arsenic)." This raises once again the likelihood that other chemicals are correspondingly more potent carcinogens in humans than in animals and gives us added incentive to reduce or eliminate exposures to those agents identified as causing cancer in laboratory animals (Huff et al., 1991; Huff, 1999b
; Tomatis et al., 1997
).
ACKNOWLEDGMENTS
We thank John Bucher and Ronald Melnick, National Institute of Environmental Health Sciences, for their helpful comments and suggestions.
NOTES
1 To whom correspondence should be addressed. Fax: (919) 558-7055. E-mail: huff1{at}niehs.nih.gov.
REFERENCES
Abernathy, C. O., Liu, Y. P., Longfellow, D., Aposhian, H. V., Beck, B., Fowler, B., Goyer, R., Menzer, R., Rossman, T., Thompson, C., and Waalkes, M. (1999). Arsenic: Health effects, mechanisms of actions, and research issues. Environ. Health Perspect. 107, 593597.[Medline]
Arnold, L. L., Cano, M., St. John, M., Eldan, M., van Gemert, M., and Cohen, S. M. (1999). Effects of dietary dimethylarsinic acid on the urine and urothelium of rats. Carcinogenesis 20, 21712179.
ATSDR (1999). Toxicological profile for arsenic (update). Agency for Toxic Substances and Disease Registry, Atlanta, GA.
Barrett, J. C., Lamb, P. W., Wang, T. C., and Lee, T. C. (1989). Mechanisms of arsenic-induced cell transformation. Biol. Trace Elem. Res. 21, 421429.[ISI][Medline]
Brown, J. L., Kitchin, K.T., and George, M. (1997). Dimethylarsinic acid treatment alters six different rat biochemical parameters: Relevance to arsenic carcinogenesis. Teratog. Carcinog. Mutagen. 17, 7184.[ISI][Medline]
Chan, P., and Huff, J. E. (1997). Arsenic carcinogenesis in animals and in humans: Mechanistic, experimental, and epidemiological evidence. Environ. Carcino. Ecotox. Revs. C15, 83122.
Cohen, S. M., Arnold, L. L., John, M. K. St., Cano, M., and van Gemert, M. Effects of dimethylarsenic acid (DMA) on urinary parameters and bladder epithelium in female F344 rats: Abstract #1086. March 1999 Society of Toxicology Annual Meeting, New Orleans, LA.
Farber, E. (1995). Cell proliferation as a major risk factor for cancer: A concept of doubtful validity. Cancer Res. 55, 37593762.[ISI][Medline]
Germolec, D. R., Spalding, J., Boorman, G. A., Wilmer, J. L., Yoshida, T., Simeonova, P. P., Bruccoleri, A., Kayama, F., Gaido, K., Tennant, R., Burleson, F., Dong, W., Lang, R. W., and Luster, M. I. (1997). Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors. Mutat. Res. 386, 209218.[ISI][Medline]
Germolec, D. R., Spalding, J., Yu, H. S., Chen, G. S., Simeonova, P. P., Humble, M. C., Bruccoleri, A., Boorman, G. A., Foley, J. F., Yoshida, T., and Luster, M. I. (1998). Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors. Am. J. Pathol. 153, 17751785.
Goering, P. L., Aposhian, H. V., Mass, M. J., Cebrian, M., Beck, B. D., and Waalkes, M. P. (1999). The enigma of arsenic carcinogenesis: Role of metabolism. Toxicol. Sci. 49, 514.[Abstract]
Huang, S. Y., Chang, C. S., Tang, J. L., Tien, H. F., Kuo, T. L., Huang, S. F., Yao, Y. T., Chou, W. C., Chung, C. Y., Wang, C. H., Shen, M. C., and Chen, Y. C. (1998). Acute and chronic arsenic poisoning associated with treatment of acute promyelocytic leukaemia. Br. J. Haematol. 103, 10921095.[ISI][Medline]
Huff, J. (1992). Chemical toxicity and chemical carcinogenesis. Is there a causal connection? A comparative morphological evaluation of 1500 experiments. IARC Sci. Publ. 116, 437475.[Medline]
Huff, J. E. (1994). Chemicals causally associated with cancers in humans and in laboratory animals: A perfect concordance. In Carcinogenesis. (M. P. Waalkes and J. M. Ward, Eds.), pp. 2537. Raven Press, New York.
Huff, J. (1995). Mechanisms, chemical carcinogenesis, and risk assessment: Cell proliferation and cancer. Am. J. Ind. Med. 27, 293300.[ISI][Medline]
Huff, J. E. (1998). Carcinogenesis results in animals predict cancer risks to humans. In Maxcy-Rosenau-Last's Public Health & Preventive Medicine, 14th ed. (R. B. Wallace, Ed.), pp. 543550, 567569. Appleton & Lange, Norwalk, CT.
Huff, J. (1999a). Value, validity, and historical development of carcinogenesis studies for predicting and confirming carcinogenic risks to humans. In Carcinogenicity Testing, Predicting, & Interpreting Chemical Effects (K. T. Kitchin, Ed.), pp. 21123. Marcel Dekker, New York.
Huff, J. (1999b). Chemicals associated with tumours of the kidney, urinary bladder, and thyroid glands from 2000 NTP long-term chemical carcinogenesis experiments in laboratory rodents. In Species Differences in Thyroid, Kidney and Urinary Bladder Carcinogenesis.( C. Capen, E. Dybing, J. Rice, and J. Wilbourn, Eds.), pp. 211225. International Agency for Research on Cancer, Lyon.
Huff, J., Chan, P., and Waalkes, M. (1998a). Arsenic carcinogenicity testing. Environ. Health Perspect. 106, A170.
Huff, J. E., Haseman, J. K., DeMarini, D. M., Eustis, S., Maronpot, R. R., Peters, A. C., Persing, R. L., Chrisp, C. E., and Jacobs, A. C. (1989). Multiple-site carcinogenicity of benzene in Fischer 344 rats and B6C3F1 mice. Environ. Health Perspect. 82, 125163.[ISI][Medline]
Huff, J., Haseman, J., and Rall, D. (1991). Scientific concepts, value, and significance of chemical carcinogenesis studies. Annu. Rev. Pharmacol. Toxicol. 31, 621652.[ISI][Medline]
Huff, J. E., and Rall, D. P. (1992). Relevance to humans of carcinogenesis results from laboratory animal toxicology studies. In Maxcy-Rosenau-Last's Public Health & Preventive Medicine, 13th ed. (J. M. Last and R. B. Wallace, Eds.), pp. 433440, 453457. Appleton & Lange, Norwalk, CT.
Huff, J., Waalkes, M., and Chan, P. (1998b). ArsenicEvidence of carcinogenicity in animals. Environ. Health Perspect. 106, A582A583.
Huff, J., Waalkes, M., Nyska, A., and Chan, P. (1999). Re: apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J. Natl. Cancer Inst. 91, 16901691.
Hutchinson, J. (1987). Arsenic and cancer. Br. Med. J. 2, 12801281.
Hutchinson, J. (1988). Diseases, Etc., of the Skin: I. On some examples of arsenic-keratosis of the skin and of arsenic-cancer. Trans. Pathol. Soc. London. 39, 352363.
IARC (1980). Arsenic and arsenic compounds. Some Metals and Metallic Compounds. In IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 23, 39141. International Agency for Research on Cancer, Lyon, France.
IARC (1987). Arsenic. In Overall Evaluations of Carcinogenicity. An Updating of IARC Monographs 1 to 42. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Suppl. 7, 100106. International Agency for Research on Cancer, Lyon, France.
Johansen, M. G., McGowan, J. P., Tu, S. H., and Shirachi, D. Y. (1984) Tumorigenic effect of dimethyl-arsinic acid in the rat. Proc. West. Pharmacol. Soc. 27, 289291.[ISI]
Lee, T. C., Oshimura, M., and Barrett, J. C. (1985). Comparison of arsenic-induced cell transformation, cytotoxicity, mutation, and cytogenetic effects in Syrian hamster embryo cells in culture. Carcinogenesis 6, 14211426.[Abstract]
Lee, T. C., Tanaka, N., Lamb, P. W., Gilmer, T. M., and Barrett, J. C. (1988). Induction of gene amplification by arsenic. Science 241, 7981.[ISI][Medline]
Li, W., Wanibuchi, H., Salim, E. I., Yamamoto, S., Yoshida, K., Endo, G., and Fukushima, S. (1998). Promotion of NCI-Black-Reiter male rat bladder carcinogenesis by dimethylarsinic acid an organic arsenic compound. Cancer Lett. 134, 2936.[ISI][Medline]
Maltoni, C., Ciliberti, A., Cotti, G., Conti, B., and Belpoggi, F. (1989). Benzene, an experimental, multipotential carcinogen: Results of the long-term bioassays performed at the Bologna Institute of Oncology. Environ. Health Perspect. 82, 109124.[ISI][Medline]
Ng, J. C., Seawright, A. A., Qi, L., Garnett, C. M., Moore, M. R., and Chiswell, B. (1998). Tumours in mice induced by chronic exposure of high arsenic concentration in drinking water: Abstract. Third International Conference on Arsenic Exposure and Health Effects. San Diego, CA, USA. July 1998.
NTP (1994). Minutes of the National Toxicology Program's Interagency Committee for Chemical Evaluation and Coordination (ICCEC) Meeting on 1 June 1999.
NTP (1999). Minutes of the National Toxicology Program's Interagency Committee for Chemical Evaluation and Coordination (ICCEC) Meeting on 14 December 1994.
NTP (2000). Arsenic and certain arsenic compounds. In Reports on Carcinogens, First and Subsequent 2nd9th (19802000), pp. 1719. National Toxicology Program, Research Triangle Park, NC.
Stayner, L. T., Danoivic, D. A., and Lemen, R. A. (1997). Asbestos-related cancer and the amphibole hypothesis. Amer. J. Pub. Health 87, 691.[ISI][Medline]
Tomatis, L., Aitio, A., Wilbourn, J., and Shuker, L. (1989). Human carcinogens so far identified. Jpn. J. Cancer Res. 80, 795807.[ISI][Medline]
Tomatis, L, Huff, J., Hertz-Picciotto, I., Sandler, D. P., Bucher, J., Boffetta, P., Axelson, O., Blair. A., Taylor, J., Stayner, L., and Barrett, J. C. (1997). Avoided and avoidable risks of cancer. Carcinogenesis 18, 97105.[Abstract]
Vahter, M. (1994). Species differences in the metabolism of arsenic compounds. Appl. Organometal. Chem. 8, 175182.[ISI]
van Gemert, M., and Eldan, M. (1998). Chronic carcinogenicity assessment of cacodylic acid: Abstract, p. 113. Third International Conference on Arsenic Exposure and Health Effects, July 1998, San Diego, CA.
Wanibuchi, H., Wei, M., Yamamoto, S., Li, W., and Fukushima, S. (1999). Carcinogenicity of an organic arsenical, dimethyl-arsinic acid and related arsenicals in rat urinary bladder. Proc. AACR 40, 349.
Wanibuchi, H., Yamamoto, S., Chen, H., Yoshida, K., Endo, G., Hori ,T., and Fukushima, S. (1996). Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl)nitrosamine induced urinary bladder carcinogenesis in rats. Carcinogenesis 17, 24352439.[Abstract]
Wei, M., Wanibuchi, H., Yamamoto, S., Li, W., and Fukushima, S. (1999). Urinary bladder carcinogenicity of dimethylarsinic acid in male F344 rats. Carcinogenesis 20, 18731876.
Weinstein, I. B. (1991). Mitogenesis is only one factor in carcinogenesis. Science 251, 387388.[ISI][Medline]
Weinstein, I. B. (1992). Toxicity, cell proliferation, and carcinogenesis. Mol. Carcinog. 5, 23.[ISI][Medline]
Wilbourn, J., Haroun, L., Heseltine, E., Kaldor, J., Partensky, C., and Vainio, H. (1986). Response of experimental animals to human carcinogens: An analysis based upon the IARC Monographs Programme. Carcinogenesis 7, 18531863.[Abstract]
Yamamoto, S., Konishi, Y., Matsuda, T., Murai, T., Shibata, M. A., Matsui-Yuasa, I., Otani, S., Kuroda, K., Endo, G., and Fukushima, S. (1995). Cancer induction by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carcinogens. Cancer Res. 55, 12711276.[Abstract]
Yamamoto, S., Wanibuchi, H., Hori, T., Yano, Y., Matsui-Yuasa, I., Otani, S., Chen, H., Yoshida, K., Kuroda, K., Endo, G., and Fukushima, S. (1997). Possible carcinogenic potential of dimethylarsinic acid as assessed in rat in vivo models: a review. Mutat. Res. 386, 353361.[ISI][Medline]
Yamanaka, K, Hasegawa, A., Sawamura, R., and Okada, S. (1989). Dimethylated arsenics induce DNA strand breaks in lung via the production of active oxygen in mice. Biochem. Biophys. Res. Commun. 165, 4350.[ISI][Medline]
Yamanaka, K., Ohtsubo, K., Hasegawa, A., Hayashi, H., Ohji, H., Kanisawa, M., and Okada, S. (1996). Exposure to dimethylarsinic acid, a main metabolite of inorganic arsenics, strongly promotes tumorigenesis initiated by 4-nitroquinoline 1-oxide in the lungs of mice. Carcinogenesis 17, 767770.[Abstract]
Yamanaka, K., Hayashi, H., Tachikawa, M., Kato, K., Hasegawa, A., Oku, N., and Okada, S. (1997). Metabolic methylation is a possible genotoxicity-enhancing process of inorganic arsenics. Mutat. Res. 394, 95101.[ISI][Medline]
Zhu, X. H., Shen, Y. L., Jing, Y. K., Cai, X., Jia, P. M., Huang, Y., Tang, W., Shi, G. Y., Sun, Y. P., Dai, J., Wang, Z. Y., Chen, S. J., Zhang, T. D., Waxman, S., Chen, Z., and Chen, G. Q. (1999). Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J. Natl. Cancer Inst. 91, 772778.