6.3 Non-genotoxic carcinogens

Non-genotoxic carcinogens promote cancer without directly damaging DNA. They work through diverse mechanisms like altering cell growth, death, and differentiation. Understanding these substances is crucial for assessing cancer risk and developing strategies to minimize exposure.

These carcinogens can act through receptors or other pathways, causing epigenetic changes, disrupting hormones, suppressing immunity, or triggering inflammation. Examples include hormones, peroxisome proliferators, and tumor promoters. Assessing their risks is challenging due to complex dose-response relationships and species differences.

Definition of non-genotoxic carcinogens

• Non-genotoxic carcinogens are substances that promote cancer development without directly damaging DNA, unlike genotoxic carcinogens which directly interact with and damage genetic material
• These carcinogens often have diverse mechanisms of action that influence cell proliferation, apoptosis, and differentiation, contributing to the multistage process of carcinogenesis
• Understanding non-genotoxic carcinogens is crucial in toxicology for assessing cancer risk and developing preventive strategies for minimizing exposure to these substances

Mechanisms of action

Receptor-mediated vs non-receptor-mediated

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• Receptor-mediated mechanisms involve the binding of non-genotoxic carcinogens to specific cellular receptors (estrogen receptors), leading to alterations in gene expression and cell signaling pathways
• Non-receptor-mediated mechanisms encompass various processes such as epigenetic modifications, endocrine disruption, and inflammation that contribute to carcinogenesis without direct receptor interactions
• Distinguishing between these two broad categories helps in understanding the diverse ways non-genotoxic carcinogens can promote cancer development

Epigenetic modifications

• Non-genotoxic carcinogens can induce epigenetic changes, which are heritable modifications to gene expression without altering the DNA sequence itself
• These modifications include DNA methylation, histone modifications, and non-coding RNA regulation, which can lead to the silencing of tumor suppressor genes or the activation of oncogenes
• Epigenetic alterations by non-genotoxic carcinogens can result in long-lasting effects on cell behavior and contribute to the development of cancer (bisphenol A, diethylstilbestrol)

Endocrine disruption

• Some non-genotoxic carcinogens act as endocrine disruptors, interfering with the normal functioning of hormonal systems in the body
• These substances can mimic or antagonize the effects of endogenous hormones (estrogens, androgens), leading to imbalances in cell growth and differentiation
• Endocrine disruption by non-genotoxic carcinogens is particularly relevant for hormone-sensitive tissues such as the breast, prostate, and thyroid, where dysregulation can promote the development of cancer (polychlorinated biphenyls, phthalates)

Immunosuppression

• Certain non-genotoxic carcinogens can suppress the immune system, compromising the body's ability to detect and eliminate transformed or precancerous cells
• Immunosuppression can occur through various mechanisms, such as the inhibition of immune cell function, the induction of regulatory T cells, or the modulation of cytokine production
• Non-genotoxic carcinogens that cause immunosuppression can create a permissive environment for the growth and progression of cancer cells (cyclosporine, azathioprine)

Inflammation and oxidative stress

• Non-genotoxic carcinogens can induce chronic inflammation and oxidative stress, which are known to contribute to the development of cancer
• Inflammation promotes the release of growth factors, cytokines, and reactive oxygen species that can stimulate cell proliferation and survival, as well as cause DNA damage and mutations
• Oxidative stress results from an imbalance between the production of reactive oxygen species and the cell's antioxidant defenses, leading to oxidative damage to macromolecules and cellular structures
• Non-genotoxic carcinogens that induce inflammation and oxidative stress can create a pro-tumorigenic microenvironment that favors the initiation and progression of cancer (asbestos, alcohol)

Examples of non-genotoxic carcinogens

Hormones and hormone mimics

• Hormones and hormone mimics are a significant class of non-genotoxic carcinogens that can promote the development of hormone-dependent cancers
• Endogenous hormones such as estrogens and androgens can stimulate the growth and proliferation of target tissues (breast, prostate), and their dysregulation can contribute to carcinogenesis
• Synthetic hormone mimics, also known as endocrine disruptors, can interfere with the normal functioning of hormonal systems and promote cancer development (diethylstilbestrol, bisphenol A)

Peroxisome proliferators

• Peroxisome proliferators are a group of non-genotoxic carcinogens that induce the proliferation of peroxisomes, cellular organelles involved in lipid metabolism and detoxification
• These compounds, which include certain pharmaceuticals (fibrates) and industrial chemicals (phthalates), can activate the peroxisome proliferator-activated receptor (PPAR) and alter gene expression
• Chronic exposure to peroxisome proliferators has been associated with the development of liver tumors in rodents, although the relevance to human cancer risk remains uncertain

Cytotoxic agents

• Cytotoxic agents are non-genotoxic carcinogens that cause cell death and tissue damage, leading to compensatory cell proliferation and an increased risk of cancer
• These agents can induce necrosis or apoptosis in target tissues, triggering an inflammatory response and the release of growth factors that stimulate the proliferation of surviving cells
• Examples of cytotoxic non-genotoxic carcinogens include chloroform, which causes liver and kidney tumors in rodents, and saccharin, which induces bladder tumors in rats

Tumor promoters

• Tumor promoters are non-genotoxic carcinogens that enhance the growth and progression of initiated or precancerous cells, often by stimulating cell proliferation and inhibiting apoptosis
• These compounds do not directly cause DNA damage but instead create a favorable environment for the expansion of transformed cell populations
• Classic examples of tumor promoters include phorbol esters (TPA), which activate protein kinase C signaling, and phenobarbital, which promotes liver tumor development in rodents

Dose-response relationships

Threshold vs non-threshold effects

• The dose-response relationships of non-genotoxic carcinogens can exhibit either threshold or non-threshold effects, depending on the specific mechanism of action
• Threshold effects occur when there is a dose below which no adverse effects are observed, and the carcinogenic response only manifests above a certain exposure level
• Non-threshold effects, on the other hand, assume that any level of exposure carries some degree of cancer risk, with the risk increasing as the dose increases
• Understanding the nature of the dose-response relationship is crucial for setting exposure limits and assessing the potential cancer risk associated with non-genotoxic carcinogens

Low-dose extrapolation challenges

• Extrapolating the cancer risk from high-dose animal studies to low-dose human exposures poses significant challenges for non-genotoxic carcinogens
• Non-genotoxic carcinogens often exhibit complex dose-response relationships, with potential differences in the mechanisms of action at high and low doses
• Low-dose effects may involve subtle changes in gene expression, cell signaling, or tissue organization that are difficult to detect and quantify in experimental settings
• Improving low-dose extrapolation methods and incorporating mechanistic data are essential for refining the risk assessment of non-genotoxic carcinogens and protecting public health

Target organs and tissues

Liver as a common target

• The liver is a common target organ for non-genotoxic carcinogens due to its central role in metabolism and detoxification
• Many non-genotoxic carcinogens, such as peroxisome proliferators (fibrates) and cytotoxic agents (chloroform), induce liver tumors in rodent models
• The susceptibility of the liver to non-genotoxic carcinogens may be attributed to its high metabolic activity, the presence of specific receptors (PPARs), and its ability to regenerate in response to injury

Endocrine-sensitive tissues

• Endocrine-sensitive tissues, such as the breast, prostate, and thyroid, are particularly vulnerable to the effects of non-genotoxic carcinogens that act as endocrine disruptors
• These tissues are highly responsive to hormonal stimulation, and exposure to hormone mimics or endocrine disruptors can lead to abnormal cell proliferation and an increased risk of cancer
• Examples of non-genotoxic carcinogens targeting endocrine-sensitive tissues include diethylstilbestrol (breast cancer) and polybrominated diphenyl ethers (thyroid cancer)

Species and sex differences

• The susceptibility to non-genotoxic carcinogens can vary significantly between different species and sexes, complicating the extrapolation of animal data to human cancer risk
• Some non-genotoxic carcinogens may induce tumors in specific animal models but not in others, or they may exhibit sex-specific effects due to differences in hormonal regulation or metabolic pathways
• For instance, the synthetic estrogen diethylstilbestrol induces clear cell adenocarcinoma of the vagina and cervix in women exposed in utero, but it does not cause the same effect in rodents
• Understanding species and sex differences in the response to non-genotoxic carcinogens is crucial for designing appropriate animal studies and interpreting their relevance to human health

Risk assessment challenges

Lack of genotoxicity assays

• Traditional genotoxicity assays, such as the Ames test or the micronucleus assay, are not suitable for detecting the carcinogenic potential of non-genotoxic carcinogens
• These assays focus on detecting direct DNA damage or mutations, which are not the primary mechanisms of action for non-genotoxic carcinogens
• The lack of reliable and validated assays for non-genotoxic carcinogens poses challenges for their identification and risk assessment, requiring the development of alternative testing strategies

Relevance of animal models

• The relevance of animal models for predicting the carcinogenic potential of non-genotoxic carcinogens in humans is often questioned due to species-specific differences in metabolism, receptor expression, and tissue responses
• Some non-genotoxic carcinogens may induce tumors in rodents through mechanisms that are not relevant to humans, leading to false-positive results and overestimation of human cancer risk
• For example, the peroxisome proliferator-activated receptor alpha (PPARα) agonists induce liver tumors in rodents but not in humans due to differences in PPARα expression and function
• Careful consideration of the mechanistic basis and human relevance of animal tumor findings is essential for the accurate risk assessment of non-genotoxic carcinogens

Extrapolation to human exposure

• Extrapolating the cancer risk from animal studies to human exposure scenarios is challenging for non-genotoxic carcinogens due to differences in exposure routes, durations, and levels
• Non-genotoxic carcinogens often require prolonged exposure and high doses to induce tumors in animal models, which may not be representative of typical human exposure patterns
• Additionally, the complex interplay between non-genotoxic carcinogens and other risk factors, such as genetic susceptibility, lifestyle factors, and co-exposures, can modulate the cancer risk in human populations
• Incorporating epidemiological data, when available, and using physiologically based pharmacokinetic (PBPK) modeling can help refine the extrapolation of animal data to human cancer risk assessment

Regulatory considerations

Classification and labeling

• The classification and labeling of non-genotoxic carcinogens are essential for communicating their potential hazards and ensuring appropriate risk management measures
• Regulatory agencies, such as the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (EPA), have established classification systems for carcinogens based on the strength of evidence from animal and human studies
• Non-genotoxic carcinogens may be classified as probable or possible human carcinogens, depending on the available data and the weight of evidence for their carcinogenic potential
• Accurate classification and labeling of non-genotoxic carcinogens are crucial for informing risk assessment, regulatory decision-making, and public health protection

Exposure limits and guidelines

• Setting exposure limits and guidelines for non-genotoxic carcinogens is a complex task that requires careful consideration of the available toxicological and epidemiological data
• Regulatory agencies may establish occupational exposure limits (OELs) or environmental quality guidelines to minimize the cancer risk associated with non-genotoxic carcinogens
• These limits and guidelines are often based on a combination of animal toxicity data, mechanistic information, and uncertainty factors to account for species differences and sensitive subpopulations
• Regular review and update of exposure limits and guidelines are necessary as new scientific evidence emerges and risk assessment methodologies evolve

Alternative testing strategies

• Given the limitations of traditional genotoxicity assays for detecting non-genotoxic carcinogens, alternative testing strategies are being developed to improve their identification and risk assessment
• In vitro assays that focus on key events in the carcinogenic process, such as cell transformation, epigenetic alterations, or receptor activation, can provide mechanistic insights and help prioritize compounds for further testing
• High-throughput screening (HTS) approaches, such as the U.S. EPA's ToxCast program, can rapidly assess large numbers of chemicals for their potential to interact with molecular targets or pathways relevant to non-genotoxic carcinogenesis
• Incorporating alternative testing strategies into regulatory decision-making frameworks can enhance the efficiency and effectiveness of non-genotoxic carcinogen risk assessment and support the development of safer alternatives

Prevention and mitigation strategies

Exposure reduction and control

• Reducing and controlling exposure to non-genotoxic carcinogens is a key strategy for preventing their potential adverse health effects, including cancer
• This can be achieved through various measures, such as substituting high-risk chemicals with safer alternatives, implementing engineering controls (ventilation systems) in occupational settings, and promoting the use of personal protective equipment
• Regulatory actions, such as banning or restricting the use of certain non-genotoxic carcinogens (asbestos), can also contribute to exposure reduction and public health protection
• Raising awareness about the potential hazards of non-genotoxic carcinogens and providing guidance on safe handling and disposal practices are essential for minimizing exposures in both occupational and non-occupational settings

Biomonitoring and early detection

• Biomonitoring involves the measurement of non-genotoxic carcinogens or their biomarkers in human biological samples (blood, urine) to assess exposure and potential health risks
• Early detection of exposure to non-genotoxic carcinogens can help identify at-risk populations and guide interventions to reduce or eliminate the source of exposure
• Monitoring biomarkers of effect, such as changes in gene expression, epigenetic modifications, or cellular proliferation, can provide early indicators of the carcinogenic process and inform preventive strategies
• Integrating biomonitoring data with epidemiological studies can enhance our understanding of the relationship between non-genotoxic carcinogen exposure and cancer risk in human populations

Chemoprevention approaches

• Chemoprevention involves the use of natural or synthetic compounds to prevent, delay, or reverse the carcinogenic process induced by non-genotoxic carcinogens
• Several chemopreventive agents have been identified that can modulate the activity of enzymes involved in the metabolism of non-genotoxic carcinogens (phase I and phase II enzymes), enhance antioxidant defenses, or inhibit cell proliferation and inflammation
• Examples of chemopreventive agents include natural compounds such as resveratrol (grapes) and curcumin (turmeric), as well as synthetic drugs like non-steroidal anti-inflammatory drugs (NSAIDs) and selective estrogen receptor modulators (SERMs)
• Incorporating chemoprevention strategies into high-risk populations, such as those with occupational exposures or genetic predispositions, may offer a promising approach to reducing the burden of cancer associated with non-genotoxic carcinogens