Chemical Carcinogens workplace risk assessment and health surveillance

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Chemical Carcinogens workplace risk assessment
and health surveillance

• Tiina Santonen 4.11.03 Paide

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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)

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Classification and labelling, cont

• 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)

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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.

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Mechanism of action of carcinogens

• genotoxic
• non-genotoxic

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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

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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

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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

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Mechanism of action of non-genotoxic carcinogens
cont

• 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
• gt 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)

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Dose-response
D O S E
linear, no threshold
non-linear, threshold
Effect
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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

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Non-genotoxic carcinogens setting of OELs

• No-observed-adverse-effect level (NOAEL) or
  Lowest-observed-adverse-effect-level (LOAEL)
• uncertainty factor
• gtOEL

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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 isnt 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

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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 gt 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

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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

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• Sulphuric acid, cont
• 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

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• 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

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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
• gt Medical surveillance has only a little value
  in the follow-up of workers

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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)

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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

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Carcinogens - Health surveillance aspects

• For example lung cancer screening in the case of
  genotoxic lung carcinogens like hexavalent
  chromium
• Periodic chest X-rays ?
• insensitivity gt 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.

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• gt 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 gt10
  years
• gt 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.