The Risk of Oral Cancer and the High Consumption of Thermally Processed Meat Containing Mutagenic and Carcinogenic Compounds.

The International Agency for Research on Cancer has classified the consumption of heat-processed meat as a direct human carcinogen and the consumption of red meat as a probable carcinogen. Mutagenic and carcinogenic compounds present in meat dishes include, among others, polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs). These compounds can cause the development of gastrointestinal cancer. Oral cancer is one of the world's research priorities due to the ever-increasing incidence rate. However, the effect of diet on oral cancer is still a poorly recognized issue. The aim of this study was to assess the relationship between the risk of oral cancer and dietary ingredients with a particular emphasis on red meat and thermally processed meat. This study was conducted among patients with oral cancer in 2022 and 2023. The shortened standardized Food Frequency Questionnaire (FFQ) and a multivariate regression statistical analysis were used. The high consumption of red meat in general and thermally processed meat, especially smoked, fried, roasted and boiled, increases the risk of oral cavity cancer. Limiting the consumption of meat products and modifying the methods of preparing meat dishes may reduce exposure to carcinogenic compounds from the diet and thus reduce the risk of developing oral cancer.

EDUCATION FROM DERMATOLOGISTS: THE SIMULTANEOUSLY DEVELOPMENT OF 16 KERATINOCYTIC CANCERS AFTER USE OF METFORMIN IN COMBINATION WITH LOSARTAN/ HYDROCHLOROTHIAZIDE, METOPROLOL AND NIFEDIPINE- IMPORTANT LINKS TO DRUG RELATED (PHOTO)-NITROSO-CARCINOGENESIS AND ONCOPHARMACOGENESIS.

Oncopharmacogenesis and Drug-Induced Skin cancer related Nitrosogenesis are newly introduced concepts in the medical literature that owe their genesis or presence to the carcinogens/ mutagens, also known as nitrosamines/NDSRIs, which are present in a heterogeneous class of drugs. The contribution to the origin of these 2 concepts is entirely due to 1) the functions and efficacy of FDA in terms of control and identification of these carcinogens, and 2) the establishment of clinicopathological correlations by the dermatologists, occurring during drug intake. According to recent FDA data, the concentration of NDMA in just one metformin tablet could be up to more than 5-fold increased. The intake of 3 to 6 tablets per day should result in a carcinogen intake that is 15 to 30 times elevated within the day and within the monomedication alone. It is these circumstances that paraphrase/ ˝betonate˝ concepts such as Onco-Pharmacogenesis and Drug-mediated Nitrosogenesis of skin cancer. Although not officially declared, these mutagens are present and have been in forced tolerance mode for the last 30-40 years. And after their intake, multiple cancers have been found to develop. The concomitant use of other nitrosamine-contaminated drugs such as losartan/hydrochlorothiazide, metoprolol and nefidipine should certainly not be surprising when it could also be associated with the development of exactly 16 keratinocytic tumours as in the case presented by us. Recent evidence in medical literature has linked the nitrosamine N-nitrosomorpholine (NMOR) with the direct development of its subsequent mutagenic action in rodents following irradiation with UVA. This fact leaves open the question of the potentially available photocarcinogenic action of the other nitrosamines in humans found in medicinal preparations. This is what necessitates a clarification of the concept of Photo-Nitroso-Carcinogenesis/ Oncogenesis in humans and its relationship to skin cancer. The overlap of the mutational patterns of some of the nitrosamine-induced mutations in target genes such as p53 and RAS oncogenes, with those of UV light-induced mutations - or practically the same ones mentioned above, suggest a possible significant role of the Drug-Induced Photo-Nitroso-Carcinogenesis of keratinocyte cancer in the context of Onco-Pharmacogenesis. Future analyses should focus on elucidating the photocarcinogenic effect of nitrosamines in drug preparations and differentiating Skin cancer Nitrosogenesis from ˝pure˝ Photo-Carcinogenesis and Nitroso-Photo-Carcinogenesis. The localization of the tumors in the area of the UV-exposed sites within the potential/actual contamination of the 4 preparations (simultaneously) in the described patient are indicative of a possible pathogenetic influence in the context of the already mentioned Nitroso-(Photo)carcinogenesis. Polycontamination of polymedication remains a so far unresolvable problem.

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency.

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.g., ß-carbon), and other reactive species can form following initial bioactivation, although these alternative pathways tend to decrease rather than enhance carcinogenic potency. The activation pathway, oxidative dealkylation, is a common reaction in drug metabolism and evidence indicates that the carbonyl byproduct, e.g., formaldehyde, does not contribute to the toxic properties of N-nitrosamines. Nitric oxide (NO), a side product of denitrosation, can similarly be discounted as an enhancer of N-nitrosamine toxicity based on carcinogenicity data for substances that act as NO-donors. However, not all N-nitrosamines are potent rodent carcinogens. In a significant number of cases, there is a potency overlap with non-N-nitrosamine carcinogens that are not in the Cohort of Concern (CoC; high-potency rodent carcinogens comprising aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds), while other N-nitrosamines are devoid of carcinogenic potential. In this context, mutagenicity is a useful surrogate for carcinogenicity, as proposed in the ICH M7 (R2) (2023) guidance. Thus, in the safety assessment and control of N-nitrosamines in medicines, it is important to understand those complementary attributes of mechanisms of mutagenicity and structure-activity relationships that translate to elevated potency versus those which are associated with a reduction in, or absence of, carcinogenic potency.

An atlas of epithelial cell states and plasticity in lung adenocarcinoma.

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.

Chronic exposure to low levels of phenanthrene induces histological damage and carcinogenic risk in the uterus of female mice.

Phenanthrene (Phe), a polycyclic aromatic hydrocarbon with low molecular weight, is detected in the environment at high frequency. To study the toxic effects of Phe on the uterine structure and function, female Kunming mice were exposed to Phe (0.05, 0.5, 5 ng/mL) for 270 days by drinking water. Pathological alterations and their action pathways were analyzed using immunohistochemical and biomolecular technology. Phe significantly increased the percentage of blood vessel area, the number of endometrial neutrophils (indicating the occurrence of inflammation), collagen deposition (indicating fibrosis), and the percentage of Ki-67-positive cells (indicating carcinogenesis) in the uterus. Transcriptome sequencing identified differentially expressed genes that were mainly enriched in some signaling pathways, including inflammation and carcinogenesis, suggesting a carcinogenic risk in the Phe-exposed uterus. Elevated serum estrogen levels and decreased progesterone levels exhibited a disturbance of steroid hormone balance, which might be related to uterine damage. Upregulated protein levels of uterine androgen receptor and estrogen receptor α were linked to the pathological effects. Most of the effects exhibited a nonmonotonic dose response, which might be attributed to the corresponding change in the serum levels of Phe. The results suggest that exposure to low levels of Phe could exert adverse effects on the uterus.

An integrated in vitro carcinogenicity test that distinguishes between genotoxic carcinogens, non-genotoxic carcinogens, and non-carcinogens.

Chemical safety testing plays a crucial role in product and pharmacological development, as well as chemoprevention; however, in vitro genotoxicity safety tests do not always accurately predict the chemicals that will be in vivo carcinogens. If chemicals test positive in vitro for genotoxicity but negative in vivo, this can contribute to unnecessary testing in animals used to confirm erroneous in vitro positive results. Current in vitro tests typically evaluate only genotoxicity endpoints, which limits their potential to detect non-genotoxic carcinogens. The frequency of misleading in vitro positive results can be high, leading to a requirement for more informative in vitro tests. It is now recognized that multiple-endpoint genotoxicity testing may aid more accurate detection of carcinogens and non-carcinogens. The objective of this review was to evaluate the utility of our novel, multiple-endpoint in vitro test, which uses multiple cancer-relevant endpoints to predict carcinogenic potential. The tool assessed micronucleus frequency, p53 expression, p21 expression, mitochondrial respiration, cell cycle abnormalities and, uniquely, cell morphology changes in human lymphoblastoid cell lines, TK6 and MCL-5. The endpoints were used to observe cellular responses to 18 chemicals within the following categories: genotoxic carcinogens, non-genotoxic carcinogens, toxic non-carcinogens, and misleading in vitro positive and negative agents. The number of endpoints significantly altered for each chemical was considered, alongside the holistic Integrated Signature of Carcinogenicity score, derived from the sum of fold changes for all endpoints. Following the calculation of an overall score from these measures, carcinogens exhibited greater potency than non-carcinogens. Genotoxic carcinogens were generally more potent than non-genotoxic carcinogens. This novel approach therefore demonstrated potential for correctly predicting whether chemicals with unknown mechanism may be considered carcinogens. Overall, while further validation is recommended, the test demonstrates potential for the identification of carcinogenic compounds. Adoption of the approach could enable reduced animal use in carcinogenicity testing.

An umbrella review of the evidence associating occupational carcinogens and cancer risk at 19 anatomical sites.

Occupational exposure to carcinogens of increasing cancer risk have been extensively suggested. A robust assessment of these evidence is needed to guide public policy and health care. We aimed to classify the strength of evidence for associations of 13 occupational carcinogens (OCs) and risk of cancers. We searched PubMed and Web of Science up to November 2022 to identify potentially relevant studies. We graded the evidence into convincing, highly suggestive, suggestive, weak, or not significant according to a standardized classification based on: random-effects p value, number of cancer cases, 95% confidence interval of largest study, heterogeneity between studies, 95% prediction interval, small study effect, excess significance bias and sensitivity analyses with credibility ceilings. The quality of meta-analysis was evaluated by AMSTAR 2. Forty-eight articles yielded 79 meta-analyses were included in current umbrella review. Evidence of associations were convincing (class I) or highly suggeastive (class II) for asbestos exposure and increasing risk of lung cancer among smokers (RR = 8.79, 95%CI: 5.81-13.25 for cohort studies and OR = 8.68, 95%CI: 5.68-13.24 for case-control studies), asbestos exposure and increasing risk of mesothelioma (RR = 4.61, 95%CI: 2.57-8.26), and formaldehyde exposure and increasing risk of sinonasal cancer (RR = 1.68, 95%CI: 1.38-2.05). Fifteen associations were supported by suggestive evidence (class III). In summary, the current umbrella review found strong associations between: asbestos exposure and increasing risk of lung cancer among smokers; asbestos exposure and increasing risk of mesothelioma; and formaldehyde exposure and higher risk of sinonasal cancer. Other associations might be genuine, but substantial uncertainty remains.

Circ0087385 promotes DNA damage in benzo(a)pyrene-induced lung cancer development by upregulating CYP1A1.

Increasing environmental genotoxic chemicals have been shown to induce epigenetic alterations. However, the interaction between genetics and epigenetics in chemical carcinogenesis is still not fully understood. Here, we constructed an in vitro human lung carcinogenesis model (16HBE-T) by treating human bronchial epithelial cells with a typical significant carcinogen benzo(a)pyrene (BaP). We identified a novel circular RNA, circ0087385, which was overexpressed in 16HBE-T and human lung cancer cell lines, as well as in lung cancer tissues and serum exosomes from lung cancer patients. The upregulated circ0087385 after exposure to BaP promoted DNA damage in the early stage of chemical carcinogenesis and affected the cell cycle, proliferation, and apoptosis of the malignantly transformed cells. Overexpression of circ0087385 enhanced the expression of cytochrome P450 1A1 (CYP1A1), which is crucial for metabolically activating BaP. Interfering with circ0087385 or CYP1A1 reduced the levels of ultimate carcinogen benzo(a)pyrene diol epoxide (BPDE) and BPDE-DNA adducts. Interfering with CYP1A1 partially reversed the DNA damage induced by high expression of circ0087385, as well as decreased the level of BPDE and BPDE-DNA adducts. These findings provide novel insights into the interaction between epigenetics and genetics in chemical carcinogenesis which are crucial for understanding the epigenetic and genetic toxicity of chemicals.

Risk characterization of N-nitrosodimethylamine in pharmaceuticals.

Since 2018, N-nitrosodimethylamine (NDMA) has been a reported contaminant in numerous pharmaceutical products. To guide the pharmaceutical industry, FDA identified an acceptable intake (AI) of 96 ng/day NDMA. The approach assumed a linear extrapolation from the Carcinogenic Potency Database (CPDB) harmonic-mean TD50 identified in chronic studies in rats. Although NDMA has been thought to act as a mutagenic carcinogen in experimental animals, it has not been classified as a known human carcinogen by any regulatory agency. Humans are exposed to high daily exogenous and endogenous doses of NDMA. Due to the likelihood of a threshold dose for NDMA-related tumors in animals, we believe that there is ample scientific basis to utilize the threshold-based benchmark dose or point-of-departure (POD) approach when estimating a Permissible Daily Exposure limit (PDE) for NDMA. We estimated that 29,000 ng/kg/day was an appropriate POD for calculating a PDE. Assuming an average bodyweight of 50 kg, we expect that human exposures to NDMA at doses below 5800 ng/day in pharmaceuticals would not result in an increased risk of liver cancer, and that there is little, if any, risk for any other type of cancer, when accounting for the mode-of-action in humans.

Differential effect of the duration of exposure on the carcinogenicity of cadmium in MCF10A mammary epithelial cells.

The carcinogenic role of cadmium (Cd2+) in breast cancer is still debatable. Current data points to duration of exposure as the most important element. In our study, we designed an in vitro model to investigate the effects of 3 weeks versus 6 weeks of low-level CdCl2 exposure on MCF10A cells. Our results demonstrated that after 3 weeks of CdCl2 exposure the cells displayed significant changes in the DNA integrity, but there was no development of malignant features. Interestingly, after 6 weeks of exposure, the cells significantly increased their invasion, migration and colony formation capacities. Additionally, MCF10A cells exposed for 6 weeks to CdCl2 had many dysregulated genes (4905 up-regulated and 4262 down-regulated). As follows, Cd-induced phenotypical changes are accompanied by a profound modification of the transcriptomic landscape. Furthermore, the molecular alterations driving carcinogenesis in MCF10A cells exposed to CdCl2 were found to be influenced by the duration of exposure, as in the case of MEG8. This long non-coding RNA was down-regulated at 3 weeks, but up-regulated at 6 weeks of exposure. In conclusion, even very low levels of Cd (0.5 µM) can have significant carcinogenic effects on breast cells in the case of subchronic exposure.

Toward a comprehensive life-cycle carcinogenic impact assessment: A statistical regression approach based on cancer burden.

The current approach to life cycle carcinogenic impact assessment (LCCA) is hindered by its static and linear characteristics. This situation prevents the accurate prediction of the incidence, associated damage, and potential economic burden of cancer. This study explores a highly comprehensive pathway for LCCA assessment. It uses the impacts of Tracheal, bronchus, and lung (TBL) predicted by the LCCA of China's coal power industry through a screened statistical regression model as the research target. The latest global burden of disease estimates is utilized to quantify the health damage from TBL incidence, whereas an approach combining the actual cost of health and human capital is applied to further assess the economic burden of TBL. Findings indicate that the traditional and static LCCA method, which relies on animal toxicity data, can lead to underestimations in actual LCCA. The interaction among spatiotemporal meteorological factors, epidemiological cancer disease burden, and socioeconomic behaviors allows exhibits nonlinearity due to the changes in the combined toxicity of mixed key substances. Following the active implementation of ultralow emission and energy-saving transformations in China's coal power industry, the national percentage of TBL cancer incidence caused by pollutants from the coal power industry decreased from 25.2 % in 2004 to 11.5 % in 2020. Results indicate that the established dynamic LCCA model based on temporal and spatial climate, socioeconomic, and epidemiological cancer data can be feasibly employed for the accurate impact evaluation and mitigation of carcinogens in practical applications.

[Introduction to carcinogenesis of nickel compounds in ILO criteria for Diagnosis and Exposure Standard for Occupational Diseases].

International Agency for Research on Cancer (IARC) classifies nickel compounds as Class Ⅰ carcinogens. International Labour Organization (ILO) also lists nickel compounds as carcinogenic factors of occupational cancer. At present, China is revising the Classification and Catalogue of Occupational Diseases, and cancer caused by nickel compounds may also be included in the statutory occupational diseases. The Diagnostic and Exposure Standards for Occupational Diseases published by ILO in 2022 discussed the pathogenic characteristics, occupational exposure, main health effects, diagnostic criteria and key preventive measures of nickel compounds in detail. This article mainly introduces its contents, in order to provid a basis for the formulation of relevant standards in China.

Assessing the carcinogenic and non-carcinogenic health risks of metals in the drinking water of Isfahan, Iran.

Metals are significant contributors to water pollution, posing serious threats to human health. This study aims to assess the carcinogenic and non-carcinogenic health risks associated with metals in Isfahan drinking water. Eighty water samples were randomly collected from the city's distribution network between January and March 2020-2021. Inductively coupled plasma Optical Emission Spectrometry was used to measure toxic metals, namely Pb, Cr, Cd, Ni, and As concentrations. Results revealed that the mean concentration of Ni (70.03 µg/L) exceeded the WHO reference value (70 µg/L), while the other metals were below the standard values. The average chronic daily intake order of toxic metals was Ni > Cr > Pb > As > Cd. Non-carcinogenic risk assessment through hazard quotient (HQ) and hazard index (HI) demonstrated that both THI for adults (HQingestion + HQdermal = 4.02E-03) and THI for children (HIingestion + HIdermal = 3.83E-03) were below the acceptable limit (less than 1). This indicated no non-carcinogenic risk to residents through water ingestion or dermal exposure. However, findings indicated that the ingestion route was the primary exposure pathway, with HQ values for ingestion exceeding HQ values for dermal adsorption. Carcinogenic risk assessment showed that the risk associated with As metal exceeded the acceptable limit (1 × 10-6). Therefore, implementing treatment improvement programs and appropriate control measures is essential to safeguard the health of Isfahan City residents.

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Application of duplex sequencing to evaluate mutagenicity of aristolochic acid and methapyrilene in Fisher 344 rats.

Duplex sequencing (DS) is an error-corrected next-generation sequencing (NGS) method that can overcome notorious high error rate from the process of NGS and detect ultralow-frequency mutations. In this study, we evaluated the mutagenicity of aristolochic acid, a known genotoxic carcinogen, and methapyrilene, a known nongenotoxic carcinogen using DS. Four male Fisher 344 rats were treated with aristolochic acid, methapyrilene, or the vehicle control for 6 weeks, liver tissues were collected one day after the treatment, and the DNA was isolated for analysis. The mutation frequency for the aristolochic acid-treated group was significantly increased over the vehicle control (44-fold), whereas no significant difference in the mutation frequency was observed between the methapyrilene-treated and the control groups. The primary type of mutation induced by aristolochic acid was A:T > T:A transversion, which occurred frequently at ApT sites, whereas the major type of mutation in the control and methapyrilene-treated groups was G:C > A:T transition, which occurred frequently at CpG sites. These findings are consistent with previously published data obtained with other in vivo mutation assays. Thus, our results suggest that the DS mutation assay is a promising technology for assessing mutagenicity of chemicals in vivo.

Dietary exposure to acrylamide among the Malaysian adult population.

This study aimed to estimate the Malaysian adult population's current dietary exposure and margin of exposure (MOE) to the carcinogenic processing contaminant, acrylamide. A total of 448 samples from 11 types of processed foods were collected randomly throughout Malaysia in the year 2015 and 2016. Acrylamide was analysed in samples using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) with a limit of detection (LOD) of 10 µg/kg and a limit of quantification (LOQ) of 25 µg/kg. The highest average level of acrylamide (772 ± 752 µg/kg) was found in potato crisps, followed by French fries (415 ± 914 µg/kg) and biscuits (245 ± 195 µg/kg). The total acrylamide exposure for the adult Malaysian was 0.229 and 1.77 µg/kg body weight per day for average and high consumers, respectively. The MOE were 741 and 1875 for the average consumer based on cancer and non-cancer effects of acrylamide, respectively. Meanwhile, for high consumers, the MOE is 96 for cancer and 243 for non-cancer effects. These findings indicate potential carcinogenic risks from acrylamide exposure among Malaysian adults, especially in Malay and other Bumiputra groups compared to Chinese, Indian, and other ethnic groups, while non-cancer effects appeared less concerning.

Contamination and Carcinogenic Risks of Lead in Lip Cosmetics in China.

There are growing concerns about elevated lead (Pb) levels in lip cosmetics, yet in China, the largest lip cosmetic market, recent Pb contamination in lip cosmetics and associated Pb exposure remain unclear. Here, we measured Pb levels of 29 popular lip cosmetics in China and conducted the bioaccessibility-corrected carcinogenic risk assessments and sensitivity analysis regarding Pb exposure for consumers using Monte Carlo simulation. The Pb concentrations of collected samples ranged from undetectable (< 0.05 µg/kg) to 0.21 mg/kg, all of which were well below the Pb concentration limit set for cosmetics in China (10 mg/kg). The 50th percentile incremental lifetime cancer risk (ILCR) of Pb in Chinese cosmetics (1.20E-07) was below the acceptable level (1E-06), indicating that the application of lip cosmetics and subsequent Pb exposure does not pose carcinogenic risks to consumers in most cases. The results of this study provide new insights into understanding the Pb risk in lip cosmetics.

A Practical Site-specific Method for the Detection of Bulky DNA Damages.

Helix-distorting DNA damages block RNA and DNA polymerase, compromising cell function and fate. In human cells, these damages are removed primarily by nucleotide excision repair (NER). Here, we describe damage-sensing PCR (dsPCR), a PCR-based method for the detection of these DNA damages. Exposure to DNA damaging agents results in lower PCR signal in comparison to non-damaged DNA, and repair is measured as the restoration of PCR signal over time. We show that the method successfully detects damages induced by ultraviolet (UV) radiation, by the carcinogenic component of cigarette smoke benzo[a]pyrene diol epoxide (BPDE) and by the chemotherapeutic drug cisplatin. Damage removal measured by dsPCR in a heterochromatic region is less efficient than in a transcribed and accessible region. Furthermore, lower repair is measured in repair-deficient knock-out cells. This straight-forward method could be applied by non-DNA repair experts to study the involvement of their gene-of-interest in repair. Furthermore, this method is fully amenable for high-throughput screening of DNA repair activity.

Tissue Organoid Cultures Metabolize Dietary Carcinogens Proficiently and Are Effective Models for DNA Adduct Formation.

Human tissue three-dimensional (3D) organoid cultures have the potential to reproduce in vitro the physiological properties and cellular architecture of the organs from which they are derived. The ability of organoid cultures derived from human stomach, liver, kidney, and colon to metabolically activate three dietary carcinogens, aflatoxin B1 (AFB1), aristolochic acid I (AAI), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was investigated. In each case, the response of a target tissue (liver for AFB1; kidney for AAI; colon for PhIP) was compared with that of a nontarget tissue (gastric). After treatment cell viabilities were measured, DNA damage response (DDR) was determined by Western blotting for p-p53, p21, p-CHK2, and γ-H2AX, and DNA adduct formation was quantified by mass spectrometry. Induction of the key xenobiotic-metabolizing enzymes (XMEs) CYP1A1, CYP1A2, CYP3A4, and NQO1 was assessed by qRT-PCR. We found that organoids from different tissues can activate AAI, AFB1, and PhIP. In some cases, this metabolic potential varied between tissues and between different cultures of the same tissue. Similarly, variations in the levels of expression of XMEs were observed. At comparable levels of cytotoxicity, organoids derived from tissues that are considered targets for these carcinogens had higher levels of adduct formation than a nontarget tissue.