正文
【1】英文缩写：PhIP
【2】英文全名：2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-b]PYRIDINE
【3】中文译名：2-氨基-1-甲基-6-苯丙咪唑[4，5-b]吡啶)
【4】评估工具：IPCS INCHEM ---- is an invaluable tool for those concerned with chemical safety and the sound management of chemicals.
Produced through cooperation between the International Programme on Chemical Safety (IPCS) and the Canadian Centre for Occupational Health and Safety (CCOHS); IPCS INCHEM directly responds to one of the Intergovernmental Forum on Chemical Safety (IFCS) priority actions to consolidate current, internationally peer-reviewed chemical safety-related publications and database records from international bodies, for public access. IPCS INCHEM offers quick and easy electronic access to thousands of searchable full-text documents on chemical risks and the sound management of chemicals, helping countries fulfill their commitments under （UNCED = United Nations Conference on Environment and Development）\'s Agenda 21, Chapter 19.
【5】评估标准：Evaluations of the strength of the evidence for carcinogenicity arising from human and experimental animal data are made, using standard terms.
It is recognized that the criteria for these evaluations, described below, cannot encompass all of the factors that may be relevant to an evaluation of carcinogenicity. In considering all of the relevant scientific data, the Working Group may assign the agent, mixture or exposure circumstance to a higher or lower category than a strict interpretation of these criteria would indicate.
(a) Degrees of evidence for carcinogenicity in humans and in experimental animals and supporting evidence
These categories refer only to the strength of the evidence that an exposure is carcinogenic and not to the extent of its carcinogenic activity (potency) nor to the mechanisms involved. A classification may change as new information becomes available.
An evaluation of degree of evidence, whether for a single agent or a mixture, is limited to the materials tested, as defined physically, chemically or biologically. When the agents evaluated are considered by the Working Group to be sufficiently closely related, they may be grouped together for the purpose of a single evaluation of degree of evidence.
(i) Carcinogenicity in humans
The applicability of an evaluation of the carcinogenicity of a mixture, process, occupation or industry on the basis of evidence from epidemiological studies depends on the variability over time and place of the mixtures, processes, occupations and industries. The Working Group seeks to identify the specific exposure, process or activity which is considered most likely to be responsible for any excess risk. The evaluation is focused as narrowly as the available data on exposure and other aspects permit.
The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:
Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between exposure to the agent, mixture or exposure circumstance and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence.
Limited evidence of carcinogenicity: A positive association has been observed between exposure to the agent, mixture or exposure circumstance and cancer for which a causal interpretation is considered by the Working Group to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.
Inadequate evidence of carcinogenicity: The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available.
Evidence suggesting lack of carcinogenicity: There are several adequate studies covering the full range of levels of exposure that human beings are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent, mixture or exposure circumstance and any studied cancer at any observed level of exposure. A conclusion of \'evidence suggesting lack of carcinogenicity\' is inevitably limited to the cancer sites, conditions and levels of exposure and length of observation covered by the available studies. In addition, the possibility of a very small risk at the levels of exposure studied can never be excluded.
In some instances, the above categories may be used to classify the degree of evidence related to carcinogenicity in specific organs or tissues.
(ii) Carcinogenicity in experimental animals
The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:
Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between the agent or mixture and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) in two or more independent studies in one species carried out at different times or in different laboratories or under different protocols.
Exceptionally, a single study in one species might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset.
Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; or (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the study; or (c) the agent or mixture increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential, or of certain neoplasms which may occur spontaneously in high incidences in certain strains.
Inadequate evidence of carcinogenicity: The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data on cancer in experimental animals are available.
Evidence suggesting lack of carcinogenicity: Adequate studies involving at least two species are available which show that, within the limits of the tests used, the agent or mixture is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites and levels of exposure studied.
(b) Other data relevant to the evaluation of carcinogenicity and its mechanisms
Other evidence judged to be relevant to an evaluation of carcinogenicity and of sufficient importance to affect the overall evaluation is then described. This may include data on preneoplastic lesions, tumour pathology, genetic and related effects, structure-activity relationships, metabolism and pharmacokinetics, physicochemical parameters and analogous biological agents.
Data relevant to mechanisms of the carcinogenic action are also evaluated. The strength of the evidence that any carcinogenic effect observed is due to a particular mechanism is assessed, using terms such as weak, moderate or strong. Then, the Working Group assesses if that particular mechanism is likely to be operative in humans. The strongest indications that a particular mechanism operates in humans come from data on humans or biological specimens obtained from exposed humans. The data may be considered to be especially relevant if they show that the agent in question has caused changes in exposed humans that are on the causal pathway to carcinogenesis. Such data may, however, never become available, because it is at least conceivable that certain compounds may be kept from human use solely on the basis of evidence of their toxicity and/or carcinogenicity in experimental systems.
For complex exposures, including occupational and industrial exposures, the chemical composition and the potential contribution of carcinogens known to be present are considered by the Working Group in its overall evaluation of human carcinogenicity. The Working Group also determines the extent to which the materials tested in experimental systems are related to those to which humans are exposed.
(c) Overall evaluation
Finally, the body of evidence is considered as a whole, in order to reach an overall evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of exposure.
An evaluation may be made for a group of chemical compounds that have been evaluated by the Working Group. In addition, when supporting data indicate that other, related compounds for which there is no direct evidence of capacity to induce cancer in humans or in animals may also be carcinogenic, a statement describing the rationale for this conclusion is added to the evaluation narrative; an additional evaluation may be made for this broader group of compounds if the strength of the evidence warrants it.
The agent, mixture or exposure circumstance is described according to the wording of one of the following categories, and the designated group is given. The categorization of an agent, mixture or exposure circumstance is a matter of scientific judgement, reflecting the strength of the evidence derived from studies in humans and in experimental animals and from other relevant data.
Group 1: The agent (mixture) is carcinogenic to humans.
The exposure circumstance entails exposures that are carcinogenic to humans.
This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
Group 2
This category includes agents, mixtures and exposure circumstances for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and other relevant data.
Group 2A: The agent (mixture) is probably carcinogenic to humans.
The exposure circumstance entails exposures that are probably carcinogenic to humans.
This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
【Group 2B】: The agent (mixture) is possibly carcinogenic to humans.
The exposure circumstance entails exposures that are possibly carcinogenic to humans.
--- This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
Group 3: The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.
This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.
Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans.
Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
Group 4: The agent (mixture) is probably not carcinogenic to humans.
This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals, consistently and strongly supported by a broad range of other relevant data, may be classified in this group. ( Last updated: 5 January 1999 )
【6】评估概述：International Agency for Research on Cancer (IARC) - Summaries & Evaluations：
--- 化学物质：PhIP (2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-b]PYRIDINE)
--- 归属种类：(Group 2B) （见上面有关Group 2B的分类定义）
--- 详细描述：
VOL.: 56 (1993) (p. 229)
CAS No.: 105650-23-5
Chem. Abstr. Name: 1-Methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-amine
5. Summary of Data Reported and Evaluation
5.1 Exposure data
PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) has been found in cooked meat and fish at concentrations of up to 70 ng/g. A few determinations indicated that the levels of PhIP were higher than those of IQ, MeIQ and MeIQx.
5.2 Human carcinogenicity data
No data directly relevant to an evaluation of the carcinogenicity to humans of PhIP were available. Studies on the consumption of cooked meat and fish are summarized in the monograph on IQ.
5.3 Animal carcinogenicity data
PhIP was tested for carcinogenicity in one experiment in mice and in two experiments in rats by oral administration in the diet. It increased the incidence of lymphomas in mice of each sex. In rats, it produced adenocarcinomas of the small and large intestine in males and mammary adenocarcinomas in females.
Intraperitoneal injection of PhIP to newborn male mice increased the incidence of hepatic adenomas.
A single intraperitoneal dose of PhIP after a two-thirds hepatectomy, followed by further modulating treatment, enhanced development of foci of altered hepatocytes in the livers of rats.
5.4 Other relevant data
PhIP formed DNA adducts in vivo in rats and monkeys. In rodent cells in vitro, it induced DNA damage, gene mutation and chromosomal anomalies. It induced DNA damage and mutation in bacteria.
PhIP can be metabolized by human microsomes isolated from liver and colon to a species that damages bacterial DNA.
5.5 Evaluation
There is inadequate evidence in humans for the carcinogenicity of PhIP.
There is sufficient evidence in experimental animals for the carcinogenicity of PhIP.
Overall evaluation（总体评估）：
--- PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is possibly carcinogenic to humans (Group 2B).译：PhIP【2-氨基-1-甲基-6-苯丙咪唑[4，5-b]吡啶)】对人类有致癌可能（属于2B组类）。
===========================================================================
附另一篇有关PhIP致癌研究的通讯文章摘要：
《Cancer Epidemiology Biomarkers & Prevention》 Vol. 9, 529-532, May 2000
---- 2000 American Association for Cancer Research
Short Communication
题目：2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Induces a Higher Number of Aberrant Crypt Foci in Fischer 344 (Rapid) Than in Wistar Kyoto (Slow) Acetylator Inbred Rats1
Madhu Purewal, Marco Velasco, Adrian J. Fretland, David W. Hein2 and Michael J. Wargovich
Department of Gastrointestinal Medical Oncology and Digestive Diseases, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [M. P., M. V., M. J. W.]; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40292 [A. J. F., D. W. H]; and Department of Pathology, University of South Carolina Cancer Center, Columbia, South Carolina 29203 [M. J. W.]
摘要：2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine carcinogen in the human diet and is a colon carcinogen in the rat. N-Acetyltransferase-2 (NAT2) catalyzes the conversion of PhIP and other heterocyclic amines to a DNA-reactive form. NAT2 has a polymorphic distribution in humans and other mammals, including rats. The rapid NAT2 genotype has been shown to be associated with increased colorectal cancer risk in some, but not all, human epidemiological studies. This investigation was designed to study the role of acetylator genotype in PhIP-induced colon carcinogenesis using aberrant crypt foci (ACF) as an intermediate biomarker. Five-week-old male, rapid-acetylator Fischer 344 (F344) rats and slow-acetylator Wistar-Kyoto (WKY) rats were fed the semipurified AIN76A diet with 0.01% PhIP, 0.04% PhIP, or no PhIP (control) for 8 weeks. PhIP induced ACF in both rapid- and slow-acetylator rats; 0.04% PhIP induced more ACF than 0.01% PhIP. There was no difference in the number of ACF between rapid- and slow-acetylator rats that were fed 0.01% PhIP. However, 0.04% PhIP induced 2-fold higher ACF and a greater dose-dependent increase in PhIP-induced ACF in the rapid-acetylator F344 rats compared with the slow-acetylator WKY rats.
The results support human epidemiological studies showing higher risk for colorectal cancer in rapid acetylators who frequently consume meat that is very well done.
PS：因时间有限，未能翻译成中文，非常抱歉！
【2】英文全名：2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-b]PYRIDINE
【3】中文译名：2-氨基-1-甲基-6-苯丙咪唑[4，5-b]吡啶)
【4】评估工具：IPCS INCHEM ---- is an invaluable tool for those concerned with chemical safety and the sound management of chemicals.
Produced through cooperation between the International Programme on Chemical Safety (IPCS) and the Canadian Centre for Occupational Health and Safety (CCOHS); IPCS INCHEM directly responds to one of the Intergovernmental Forum on Chemical Safety (IFCS) priority actions to consolidate current, internationally peer-reviewed chemical safety-related publications and database records from international bodies, for public access. IPCS INCHEM offers quick and easy electronic access to thousands of searchable full-text documents on chemical risks and the sound management of chemicals, helping countries fulfill their commitments under （UNCED = United Nations Conference on Environment and Development）\'s Agenda 21, Chapter 19.
【5】评估标准：Evaluations of the strength of the evidence for carcinogenicity arising from human and experimental animal data are made, using standard terms.
It is recognized that the criteria for these evaluations, described below, cannot encompass all of the factors that may be relevant to an evaluation of carcinogenicity. In considering all of the relevant scientific data, the Working Group may assign the agent, mixture or exposure circumstance to a higher or lower category than a strict interpretation of these criteria would indicate.
(a) Degrees of evidence for carcinogenicity in humans and in experimental animals and supporting evidence
These categories refer only to the strength of the evidence that an exposure is carcinogenic and not to the extent of its carcinogenic activity (potency) nor to the mechanisms involved. A classification may change as new information becomes available.
An evaluation of degree of evidence, whether for a single agent or a mixture, is limited to the materials tested, as defined physically, chemically or biologically. When the agents evaluated are considered by the Working Group to be sufficiently closely related, they may be grouped together for the purpose of a single evaluation of degree of evidence.
(i) Carcinogenicity in humans
The applicability of an evaluation of the carcinogenicity of a mixture, process, occupation or industry on the basis of evidence from epidemiological studies depends on the variability over time and place of the mixtures, processes, occupations and industries. The Working Group seeks to identify the specific exposure, process or activity which is considered most likely to be responsible for any excess risk. The evaluation is focused as narrowly as the available data on exposure and other aspects permit.
The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:
Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between exposure to the agent, mixture or exposure circumstance and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence.
Limited evidence of carcinogenicity: A positive association has been observed between exposure to the agent, mixture or exposure circumstance and cancer for which a causal interpretation is considered by the Working Group to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.
Inadequate evidence of carcinogenicity: The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available.
Evidence suggesting lack of carcinogenicity: There are several adequate studies covering the full range of levels of exposure that human beings are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent, mixture or exposure circumstance and any studied cancer at any observed level of exposure. A conclusion of \'evidence suggesting lack of carcinogenicity\' is inevitably limited to the cancer sites, conditions and levels of exposure and length of observation covered by the available studies. In addition, the possibility of a very small risk at the levels of exposure studied can never be excluded.
In some instances, the above categories may be used to classify the degree of evidence related to carcinogenicity in specific organs or tissues.
(ii) Carcinogenicity in experimental animals
The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:
Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between the agent or mixture and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) in two or more independent studies in one species carried out at different times or in different laboratories or under different protocols.
Exceptionally, a single study in one species might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset.
Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; or (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the study; or (c) the agent or mixture increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential, or of certain neoplasms which may occur spontaneously in high incidences in certain strains.
Inadequate evidence of carcinogenicity: The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data on cancer in experimental animals are available.
Evidence suggesting lack of carcinogenicity: Adequate studies involving at least two species are available which show that, within the limits of the tests used, the agent or mixture is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites and levels of exposure studied.
(b) Other data relevant to the evaluation of carcinogenicity and its mechanisms
Other evidence judged to be relevant to an evaluation of carcinogenicity and of sufficient importance to affect the overall evaluation is then described. This may include data on preneoplastic lesions, tumour pathology, genetic and related effects, structure-activity relationships, metabolism and pharmacokinetics, physicochemical parameters and analogous biological agents.
Data relevant to mechanisms of the carcinogenic action are also evaluated. The strength of the evidence that any carcinogenic effect observed is due to a particular mechanism is assessed, using terms such as weak, moderate or strong. Then, the Working Group assesses if that particular mechanism is likely to be operative in humans. The strongest indications that a particular mechanism operates in humans come from data on humans or biological specimens obtained from exposed humans. The data may be considered to be especially relevant if they show that the agent in question has caused changes in exposed humans that are on the causal pathway to carcinogenesis. Such data may, however, never become available, because it is at least conceivable that certain compounds may be kept from human use solely on the basis of evidence of their toxicity and/or carcinogenicity in experimental systems.
For complex exposures, including occupational and industrial exposures, the chemical composition and the potential contribution of carcinogens known to be present are considered by the Working Group in its overall evaluation of human carcinogenicity. The Working Group also determines the extent to which the materials tested in experimental systems are related to those to which humans are exposed.
(c) Overall evaluation
Finally, the body of evidence is considered as a whole, in order to reach an overall evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of exposure.
An evaluation may be made for a group of chemical compounds that have been evaluated by the Working Group. In addition, when supporting data indicate that other, related compounds for which there is no direct evidence of capacity to induce cancer in humans or in animals may also be carcinogenic, a statement describing the rationale for this conclusion is added to the evaluation narrative; an additional evaluation may be made for this broader group of compounds if the strength of the evidence warrants it.
The agent, mixture or exposure circumstance is described according to the wording of one of the following categories, and the designated group is given. The categorization of an agent, mixture or exposure circumstance is a matter of scientific judgement, reflecting the strength of the evidence derived from studies in humans and in experimental animals and from other relevant data.
Group 1: The agent (mixture) is carcinogenic to humans.
The exposure circumstance entails exposures that are carcinogenic to humans.
This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.
Group 2
This category includes agents, mixtures and exposure circumstances for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and other relevant data.
Group 2A: The agent (mixture) is probably carcinogenic to humans.
The exposure circumstance entails exposures that are probably carcinogenic to humans.
This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
【Group 2B】: The agent (mixture) is possibly carcinogenic to humans.
The exposure circumstance entails exposures that are possibly carcinogenic to humans.
--- This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
Group 3: The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.
This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.
Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans.
Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
Group 4: The agent (mixture) is probably not carcinogenic to humans.
This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals, consistently and strongly supported by a broad range of other relevant data, may be classified in this group. ( Last updated: 5 January 1999 )
【6】评估概述：International Agency for Research on Cancer (IARC) - Summaries & Evaluations：
--- 化学物质：PhIP (2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-b]PYRIDINE)
--- 归属种类：(Group 2B) （见上面有关Group 2B的分类定义）
--- 详细描述：
VOL.: 56 (1993) (p. 229)
CAS No.: 105650-23-5
Chem. Abstr. Name: 1-Methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-amine
5. Summary of Data Reported and Evaluation
5.1 Exposure data
PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) has been found in cooked meat and fish at concentrations of up to 70 ng/g. A few determinations indicated that the levels of PhIP were higher than those of IQ, MeIQ and MeIQx.
5.2 Human carcinogenicity data
No data directly relevant to an evaluation of the carcinogenicity to humans of PhIP were available. Studies on the consumption of cooked meat and fish are summarized in the monograph on IQ.
5.3 Animal carcinogenicity data
PhIP was tested for carcinogenicity in one experiment in mice and in two experiments in rats by oral administration in the diet. It increased the incidence of lymphomas in mice of each sex. In rats, it produced adenocarcinomas of the small and large intestine in males and mammary adenocarcinomas in females.
Intraperitoneal injection of PhIP to newborn male mice increased the incidence of hepatic adenomas.
A single intraperitoneal dose of PhIP after a two-thirds hepatectomy, followed by further modulating treatment, enhanced development of foci of altered hepatocytes in the livers of rats.
5.4 Other relevant data
PhIP formed DNA adducts in vivo in rats and monkeys. In rodent cells in vitro, it induced DNA damage, gene mutation and chromosomal anomalies. It induced DNA damage and mutation in bacteria.
PhIP can be metabolized by human microsomes isolated from liver and colon to a species that damages bacterial DNA.
5.5 Evaluation
There is inadequate evidence in humans for the carcinogenicity of PhIP.
There is sufficient evidence in experimental animals for the carcinogenicity of PhIP.
Overall evaluation（总体评估）：
--- PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is possibly carcinogenic to humans (Group 2B).译：PhIP【2-氨基-1-甲基-6-苯丙咪唑[4，5-b]吡啶)】对人类有致癌可能（属于2B组类）。
===========================================================================
附另一篇有关PhIP致癌研究的通讯文章摘要：
《Cancer Epidemiology Biomarkers & Prevention》 Vol. 9, 529-532, May 2000
---- 2000 American Association for Cancer Research
Short Communication
题目：2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Induces a Higher Number of Aberrant Crypt Foci in Fischer 344 (Rapid) Than in Wistar Kyoto (Slow) Acetylator Inbred Rats1
Madhu Purewal, Marco Velasco, Adrian J. Fretland, David W. Hein2 and Michael J. Wargovich
Department of Gastrointestinal Medical Oncology and Digestive Diseases, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [M. P., M. V., M. J. W.]; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40292 [A. J. F., D. W. H]; and Department of Pathology, University of South Carolina Cancer Center, Columbia, South Carolina 29203 [M. J. W.]
摘要：2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine carcinogen in the human diet and is a colon carcinogen in the rat. N-Acetyltransferase-2 (NAT2) catalyzes the conversion of PhIP and other heterocyclic amines to a DNA-reactive form. NAT2 has a polymorphic distribution in humans and other mammals, including rats. The rapid NAT2 genotype has been shown to be associated with increased colorectal cancer risk in some, but not all, human epidemiological studies. This investigation was designed to study the role of acetylator genotype in PhIP-induced colon carcinogenesis using aberrant crypt foci (ACF) as an intermediate biomarker. Five-week-old male, rapid-acetylator Fischer 344 (F344) rats and slow-acetylator Wistar-Kyoto (WKY) rats were fed the semipurified AIN76A diet with 0.01% PhIP, 0.04% PhIP, or no PhIP (control) for 8 weeks. PhIP induced ACF in both rapid- and slow-acetylator rats; 0.04% PhIP induced more ACF than 0.01% PhIP. There was no difference in the number of ACF between rapid- and slow-acetylator rats that were fed 0.01% PhIP. However, 0.04% PhIP induced 2-fold higher ACF and a greater dose-dependent increase in PhIP-induced ACF in the rapid-acetylator F344 rats compared with the slow-acetylator WKY rats.
The results support human epidemiological studies showing higher risk for colorectal cancer in rapid acetylators who frequently consume meat that is very well done.
PS：因时间有限，未能翻译成中文，非常抱歉！
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