Chemical Carcinogens – workplace risk assessment and health surveillance Tiina Santonen Paide

EU Classification and labelling of Carcinogens 3 Carcinogen Categories – carc. cat 1 (shown to cause cancer in humans) – carc. cat 2 (causes cancer in animal tests, and most probably also in humans) – carc. cat 3 (possibly carcinogenic, but the evidence supporting the carcinogenicity is inadequate for the classification to cat 2)

Classification and labelling, con’t R45 or R49: May cause cancer. May cause cancer by inhalation. – carc. cat 1 & 2 – labelled as toxic (T) R40: Possible risks of irreversible effects. – carc. cat 3 – labelled as harmful (Xn)

IARC Classification of carcinogens IARC class 1: The substance is carcinogenic to humans. IARC class 2A: The substance is probably carcinogenic to humans. IARC class 2B: The substance is possibly carcinogenic to humans. IARC class 3: The substance is not classifiable as to its carcinogenicity to humans IARC class 4: The substance is probably not carcinogenic to humans.

Mechanism of action of carcinogens genotoxic non-genotoxic

Genotoxic carcinogens increase tumour frequency in animal cancer bioassay AND positive results from in vitro and in vivo genotoxicity tests either direct-acting or indirectly acting genotoxic carcinogens

Non-genotoxic carcinogens usually act as tumor promoters positive in cancer bioassay in animals, but negative in genotoxicity tests The mechanism of carcinogenicity may include for example – the chronic injury and regeneration – hormonal mechanisms – increase in the cell proliferation or decrease in the cell death in target organ

Mechanism of action of non- genotoxic carcinogens – relevant to humans? some mechanisms are not considered relevant to humans Classical examples of mechanisms considered NOT relevant to humans are: – liver cancers in rodents caused by peroxisome proliferators, kidney tumours in male rats caused by the accumulation of alpha-2u-globulin in renal tubular cells, and thyroid tumours in rodents caused by agents disturbing the hormonal balance of mice and rats

Mechanism of action of non- genotoxic carcinogens – con’t tumours are seen in animal tests only at high dose levels in which there is also severe cytotoxicity in target tissues, the animal strain used in the study is known to be especially susceptible to that special type of tumours => Relevance to humans highly questionable In addition, the metabolism of the chemical may differ between the different animal species and humans modulating the sensitivity of different species to the chemical (applies also to genotoxic chemicals)

Dose-response DOSEDOSE linear, no threshold non-linear, threshold Effect

Potency of the carcinogen TD25 value used for example in the setting of EU OELs for genotoxic carcinogens TD25/1000 is considered as an acceptable risk level for genotoxic carcinogens, although also socioeconomic and technical constraines have to be taken into account in the setting of OELs

Non-genotoxic carcinogens – setting of OELs No-observed-adverse-effect level (NOAEL) or Lowest-observed-adverse-effect-level (LOAEL) uncertainty factor =>OEL

Different types of carcinogens - OELs and cancer risk Genotoxic carcinogens – no threshold, no zero risk – even if exposure levels in the workplace are below OEL, we cannot say that there isn’t any risk, because according to the current view even small amounts of genotoxic carcinogens may increase our ”mutation burden” and our susceptibility to cancer – therefore, minimization of exposure as far as possible is essential

Different types of carcinogens - OELs and cancer risk Non-genotoxic carcinogens – usually considered to possess a threshold – for example carcinogens which cause cancer via a mechanism involving chronic injury and regeneration => if the OEL is set at the level in which no chronic tissue injury is seen, the cancer risk can be regarded to be negligible

Examples Strong inorganic mists of sulphuric acid (IARC class 1) – Excess risk of laryngeal cancer in workers exposed to sulphuric acid in steel industry. – mechanism of action is chronic irritation - caused tissue injury to respiratory tract resulting in reactive stimulation of growth and promotion of cancer. – air levels of 3-4 mg/m3 are irritating to the respiratory tract, at lower exposure levels (0.5-2 mg/m3) only mild effects like sensation of acidic taste in the mouth have been reported

Sulphuric acid, con’t – exposure levels which do not cause irritation can be regarded to protect from carcinogenicity – e.g. in Finland OEL for sulphuric acid is 0.2 mg/m3 / 8 h and 1 mg/m3 /15 min Formaldehyde – a weak genotoxic agent, but its local carcinogenic potential is considered to be mediated mainly via the mechanism involving chronic injury and regeneration

Anticancer agents like cyclophosphamide – are known to cause secondary cancers in cancer patients and tumours in experimental animals – genotoxic, no threshold, therefore even low level exposures may increase our ”mutation burden”, and our susceptibility to cancer – In modern hospitals with good working practises the cancer risk of nurses and pharmacists can be regarded to be low because of the high level of protection, but if the protection and good working practises are ignored the risk increases linearly

Carcinogens - Health surveillance aspects Medical health surveillance - problems: – long latency time of cancers – cat 2 & 3 carcinogens - what kind of cancers the substance causes in humans? – is not able to prevent the disease – current cancer screening methods are not sensitive enough for early detection of cancers => Medical surveillance has only a little value in the follow-up of workers

Carcinogens - Health surveillance aspects The health surveillance of workers exposed to carcinogens should be focused on prevention Exposure assessment (e.g. industrial hygiene measurements and biomonitoring) and minimisation of exposure minimisation of other exposures which may synergistically increase the individual cancer risk with occupational exposures (e.g. tobacco smoking)

Carcinogens - Health surveillance aspects Medical health surveillance: – Need for medical health surveillance should be considered case by case by taking into the account the lenght and severity of the exposure, possible other exposures potentiating the cancer risk, and the feasibility of available methods in cancer screening

Carcinogens - Health surveillance aspects For example lung cancer screening in the case of genotoxic lung carcinogens like hexavalent chromium – Periodic chest X-rays ? – insensitivity => poor cost-benefit relationship – If screening is still performed who to screen? Longer the exposure time and higher the exposure levels, the higher the cancer risk. Also exposures to other potential lung carcinogens should be taken into the account.

=> Identification and focusing of screening to the highest risk individuals, who have worked long in poor working conditions and who probably also have history of some other carcinogenic exposures (e.g. tobacco smokers). – When to screen? The latency time for lung cancer formation is >10 years => Not justifiable to begin before 10 year have elapsed – Remember: Focus should be in prevention! Screening is needed only when prevention has failed. It does not prevent the disease or improve the prognosis.