Chemical Carcinogens by Estonian OH&S

1. Chemical Carcinogens –Chemical Carcinogens –
workplace risk assessmentworkplace risk assessment
and health surveillanceand health surveillance
Tiina Santonen 4.11.03 Paide

2. EU Classification and labellingEU 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)

3. 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)

4. IARC Classification ofIARC 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.

5. Mechanism of action ofMechanism of action of
carcinogenscarcinogens
genotoxic
non-genotoxic

6. Genotoxic carcinogensGenotoxic 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

7. Non-genotoxic carcinogensNon-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

8. 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

9. 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)

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

11. Potency of the carcinogenPotency 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

12. 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

13. Different types of carcinogensDifferent 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

14. Different types of carcinogensDifferent 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

15. ExamplesExamples
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

16. 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

17. 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

18. Carcinogens - HealthCarcinogens - 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

19. Carcinogens - HealthCarcinogens - 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)

20. Carcinogens - HealthCarcinogens - 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

21. Carcinogens - HealthCarcinogens - 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.

22. => 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.