Chemical Carcinogens – Chemical Carcinogens – workplace risk assessment workplace risk assessment

and health surveillance and health surveillance

Tiina Santonen 4.11.03 Paide

EU Classification and labelling EU Classification and labelling of Carcinogensof 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, Classification and labelling, con’tcon’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 IARC Classification of carcinogenscarcinogens

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 Mechanism of action of carcinogenscarcinogens

genotoxic

non-genotoxic

Genotoxic carcinogensGenotoxic carcinogens

increase tumour frequency in animal cancer bioassayAND

positive results from in vitro and in vivo genotoxicity tests

either direct-acting or indirectly acting genotoxic carcinogens

Non-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-Mechanism of action of non-genotoxic carcinogens – genotoxic carcinogens –

relevant to humans?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-Mechanism of action of non-genotoxic carcinogens – con’tgenotoxic 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-responseDose-response

DOSE

linear,no threshold

non-linear,threshold

Effect

Potency of the carcinogenPotency of the carcinogen

TD25 valueused for example in the setting of EU OELs

for genotoxic carcinogensTD25/1000 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 – Non-genotoxic carcinogens – setting of OELssetting of OELs

No-observed-adverse-effect level (NOAEL) or Lowest-observed-adverse-effect-level (LOAEL)

uncertainty factor

=>OEL

Different types of carcinogens Different types of carcinogens - OELs and cancer risk- 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 Different types of carcinogens - OELs and cancer risk- 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

ExamplesExamplesStrong 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 Carcinogens - Health surveillance aspectssurveillance 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 Carcinogens - Health surveillance aspectssurveillance 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 Carcinogens - Health surveillance aspectssurveillance 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 Carcinogens - Health surveillance aspectssurveillance 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.