2-Amino-1-Methyl-6-Phenylimidazo(4,5-b)Pyridine

PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols & thiosulfate. The reactivity of various alkylating agents varies greatly ... & is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness & safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp & carcinogenic wastes generated by this treatment conducted to & burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter & misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/

For more Disposal Methods (Complete) data for 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (6 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency & who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing & use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors & benches, & ... interior of fume hoods & airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple & sensitive. /Chemical Carcinogens/

PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms & sides & fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, & monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type & amt of carcinogen & efficiency with which it can be removed. /Chemical Carcinogens/

For more Preventive Measures (Complete) data for 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (9 total), please visit the HSDB record page.

PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/

Chemical model reactions were carried out to investigate the mechanism of inhibition by a citrus flavonoid, naringenin, on the formation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), the most abundant mutagenic heterocyclic amine found in foods. GC-MS showed that naringenin dose dependently reduced the level of phenylacetaldehyde, a key intermediate on the pathway to the formation of PhIP. Subsequent LC-MS analyses of samples from a wide range of model systems consisting of PhIP precursors, including phenylalanine, glucose, and creatinine, suggested that naringenin scavenged phenylacetaldehyde via adduct formation. An isotope-labeling study showed that the postulated adducts contain fragment(s) of phenylalanine origin. Direct reaction employing phenylacetaldehyde and naringenin further confirmed the capability of naringenin to form adducts with phenylacetaldehyde, thus reducing its availability for PhIP formation. Two of the adducts were subsequently isolated and purified. Their structure was elucidated by one- and two-dimensional NMR spectroscopy as 8-C-(E-phenylethenyl)naringenin (1) and 6- C-( E-phenylethenyl)naringenin (2), respectively, suggesting that C-6 and C-8 are two of the active sites of naringenin in adduct formation. These two adducts were also identified from thermally processed beef models, highlighting phenylacetaldehyde trapping as a key mechanism of naringenin to inhibit PhIP formation.

... Effects of combined treatment with sodium nitrite (NaNO(2)) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) ... were assessed with regard to mammary tumor induction in female Sprague-Dawley (SD) rats. Animals at 6 wk of age were given intragastric doses of 100 mg/kg bw of PhIP twice a week for 4 wk, during which period 0 or 0.2% NaNO(2) was administered in the drinking water. Control rats received 0.2% NaNO(2) alone for the 4 wk or non-supplemented water during the entire 48 wk experimental period, without carcinogen treatment. The first tumor in the PhIP+NaNO(2) group appeared significantly later than with PhIP alone, and during the experimental period, the incidence, multiplicity and volume of mammary tumors in this group tended towards decreased, although values did not significantly differ at the terminal sacrifice. These results indicate that NaNO(2) does not enhance PhIP-induced rat mammary carcinogenesis, rather possessing some potential for inhibition.

Male F344 5-week-old rats were X-irradiated, and 16 wk after the first dose, ... 2-amino-1 -methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) was given by intragastric intubation. Tumors in the pylorus of the glandular stomach were observed in ... 4 out of the 25 animals receiving X-rays + PhIP, 12 months after administration. No such lesions were found in the chemical or X-ray alone groups. Intestinal metaplasia and some induced tumors were positive for CDX2. It was concluded that the presence of intestinal metaplasia may increase sensitivity to the induction of gastric tumors by colon carcinogens.

This study investigates whether the previous observation that quercetin increases the transport of PhIP through Caco-2 monolayers in vitro could be confirmed in an in vivo rat model. Co-administration of 1.45 umol PhIP/kg bw and 30 umol quercetin/kg bw significantly increased the blood AUC(0-8 hr) of PhIP in rats to 131+/-14% of the AUC (0-8 hr) for rats dosed with PhIP alone. Significantly increased blood PhIP levels were detected at 15, 30, 45 and 180 min. At 4 and 8 hr post-dosing a difference in the PhIP levels in the blood between the two treatment groups was no longer observed. In vitro and in silico modeling of PhIP transport using Caco-2 cells and a previously described kinetic model for PhIP transport revealed that the relative increase in PhIP transport caused by quercetin is dependent on the concentration of the two compounds. When substituting the PhIP and quercetin concentrations used in the in vivo experiment in the kinetic model, an effect of quercetin on PhIP transport was predicted that matches the actual effect of 131% observed in vivo. It is concluded that quercetin increases the bioavailability of the pro-carcinogen PhIP in rats pointing at a potential adverse effect of this supposed beneficial food ingredient.

For more Interactions (Complete) data for 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (20 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2.0X10+4(SRC), determined from a log Kow of 2.23(2) and a regression-derived equation(3), indicates that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is expected to be immobile in soil(SRC). The estimated pKa of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is 5.4(4), indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.8X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(6). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.8X10-13 mm Hg at 25 °C(SRC), determined from a fragment constant method(7). Biodegradation in soil data were not available(SRC, 2009).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2.0X10+4(SRC), determined from a log Kow of 2.23(2) and a regression-derived equation(3), indicates that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 2.8X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 14(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation in water data were not available(SRC, 2009).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, which has an estimated vapor pressure of 8.1X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine may be removed from the air by wet or dry deposition(SRC). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine contains chromophores that absorb at wavelengths >290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine was detected in meat and chicken purchased from local Okayama, Japan markets, following cooking and analysis on the same day; in chicken, pork, well done beef and medium beef at 289, 857, 634 and 537 pg/g, respectively(1). Food purchased at a supermarket in Little Rock, AK and cooked, contained 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in pan fried beef at 426, 15200 and 161 pg/g, in pan fried beef scrapings at 82,500 pg/g, in barbequed beef at 2190 and 13,900 pg/g, beef extract at 1820 pg/g, and in barbequed chicken at 10,000 pg/g(2). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine was detected in fried beef at 15 ng/g of cooked meat(3).

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine was detected at an avg concentration of 14.1 ng/g from a diesel powered Isuzu, 4 cylinder, 3.856 L engine run on a chassis dynanometer and was detected at an avg of 173 pg/g from incineration ash collected from 4 garbage burning plants from the metropolitan area of Tokyo, Japan(1).

PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/

The Koc of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is estimated as 2.0X10+4(SRC), using a log Kow of 2.23(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is expected to be imobile in soil. The pKa of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is estimated to be 5.2(4), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

/EPIDEMIOLOGY STUDIES/ Although evidence suggests that consumption of well-done or grilled meat may be associated with increased cancer risk in humans, the data are insufficient to support the conclusion that this risk is due specifically to PhIP present in these foods ... The presence of an individual heterocyclic amine (HCA) in cooked meat is highly correlated with the presence of other HCAs and with many other constituents, including protein, animal fat, nitrosamines, and substances other than HCAs formed during cooking, such as polycyclic aromatic hydrocarbons. It is therefore difficult to establish associations between cancer risk and specific HCAs.[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-1-Methyl-6- Phenylimidazo

/EPIDEMIOLOGY STUDIES/ ... This study ... developed a modified in vitro mutagen sensitivity assay, with activated PhIP (N-OH-PhIP) as the challenge mutagen and chromosome aberrations as the endpoint, and applied it in a pilot prostate cancer (PC) case-control study of 81 cases and 84 age and ethnicity-matched controls. /The/ results showed significantly higher baseline breaks among the cases, mean +/- S.E. = 1.86 +/- 0.23 versus 0.96 +/- 0.14 in controls; P = 0.006. Individuals with high baseline breaks (dichotomized at the control median) had a 36% increased risk for PC (odds ratio (OR) = 1.36; 95% CI = 1.08-1.72). In stratified analysis, high baseline breaks was associated in younger participants (< or = 60 yr) with an OR of 1.71 (1.14-2.57) and in those with a positive family history of PC, an OR of 1.43 (0.97-2.11). PhIP treatment induced significantly higher breaks in cases, mean +/- S.E. = 5.07 +/- 0.39 versus 3.83 +/- 0.24 in controls; P = 0.05. Higher PhIP-induced breaks was associated with an overall 17% increased risk for PC (OR = 1.17; 95% CI = 1.03-1.33), a significantly increased risks (OR = 1.19; 95% CI = 1.00-1.41) among younger participants, non-smokers (OR = 1.39, 1.03-1.88) and 1.20 (1.00-1.45) among those with no family history of PC ...

/EPIDEMIOLOGY STUDIES/ To determine whether heterocyclic aromatic amine (HCA)-induced DNA damage is present in the human pancreas, immunohistochemistry and computer-assisted image analysis were used to measure PhIP-DNA adducts in 54 normal pancreatic tissues (N) from persons without pancreatic cancer and in 38 normal adjacent pancreatic tissues (A) and in 39 cancer tissues (T) from 68 patients with pancreatic adenocarcinoma. PhIP-DNA adducts were detected in 53 N, 34 A, and 39 T samples. Mean values (+/-SD) of the absorbency for PhIP staining were 0.22+/-0.04, 0.24+/-0.04, and 0.24+/-0.03 for N, A, and T samples, respectively (p = 0.004). Using the median absorbency (0.21) of the samples from normal controls as the cut-off, 71% of A and 77% of T tissues, compared with 48% of N tissues, were distributed in the higher range (p = 0.009). The odds ratio of pancreatic cancer was 3.4 (95% confidence interval 1.5-7.5, p = 0.002) for individuals with a higher level of PhIP-DNA adducts. This is the first report of the detection of PhIP-DNA adducts in human pancreatic tissue samples obtained from patients with unknown exposure to HCA. Although limited by the small sample size, these preliminary results suggest that PhIP exposure may contribute to human pancreatic cancer development.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine was detected in fish purchased from local Okayama, Japan markets, following cooking and analysis on the same day; in the skin and flesh of Pacific saury 1611 and 333 pg/g; in the skin and flesh of sardine at 816 pg/g and not detected; at 2120 and 160 pg/g in the skin and flesh of horse mackerel; in the skin and flesh of mackerel at 1595 and 226 pg/g; in the skin and flesh of salmon at 5928 and 294 pg/g; at 5377 and 658 pg/g in the skin and flesh of salted atka mackerel; 359 and 214 pg/g in seasoned eel skin and flesh; in semi-dried horse mackerel skin and flesh at 3682 and 524 pg/g(1). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine was detected in fish at 69 ng/g of cooked meat(2).

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is suggested to be a product of combustion of various materials(1) which may result in its direct release to the environment(SRC). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine has been identified in cooked meats, diesel exhaust, incineration ash and cigarette smoke(1). Its limited production and use for research purposes(2) may result in its release to the environment through various waste streams.[(1) Manabe S et al; Environ Pollut 80: 281-6 (1993) (2) DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-1-Methyl-6-Phenylimidazo

PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine)

Group 2B: Possibly carcinogenic to humans

Volume 56: (1993) Some Naturally Occurring Substances: Food Items and Constituents, Heterocyclic Aromatic Amines and Mycotoxins

1993

1992

2B, possibly carcinogenic to humans. (L135)

Mutagen present in cooked meat and fish; [Merck Index] Manufactured in small amounts for research purposes; [IARC]

No known commerical uses.[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-1-Methyl-6-Phenylimidazo

1-Methyl-6-phenyl-1H-imidazo[4,5-b]pyridin-2-amine is a food-related mutagen, reported to be the most abundant heterocyclic amine found in cooked meat and fish.

... heterocyclic amine formed during heating or cooking and /is/ found in cooked meat and fish

Most abundant of the mutagenic heterocyclic amines found in well-cooked meat and fish

PhIP is produced in small quantities for research purposes. It is formed naturally during the cooking of muscle-derived foods (meat and fish) as by-products of the Maillard (or browning) reaction. It is postulated that the amino-imidazo part of /heterocyclic amines/ (HCAs) is formed from creatine, while the remaining parts of the compound are likely formed from Strecker degradation products, such as pyridines or pyrazines, which are formed in the Maillard reaction between hexose sugars and amino acids. Formation of HCAs in food reportedly is affected by temperature, processing time, acidity, precursor concentrations, and types of amino acid present. In general, higher temperatures and longer cooking times increase the amount of HCAs produced. HCA formation also increases with cooking methods that use direct or efficient transfer of heat from the source to the food; frying or grilling of muscle meats produces more HCAs than do indirect-heat methods such as stewing, steaming, or poaching.[DHHS/National Toxicology Program; Eleventh Report on Carcinogens: 2-Amino-1-Methyl-6-Phenylimidazo