B1 TOXICOLOGY AND EPIDEMIOLOGY Flashcards
(a) Outline the principles of a prospective cohort study, as used in epidemiology. (4)
A prospective cohort study is designed to verify or deny a hypothetical link between an occupational exposure and an ill-health condition.
It involves following two similar groups (cohorts) forward in time
to evaluate their future health outcomes.
One of the groups / cohort has been (or is being) currently occupationally exposed to the agent under investigation while the other cohort has not.
For example,
workers in the micro-electronics industry who are exposed to toxic chemicals are followed forward in time (tracked) to see if there is an excess of cancers arising in future years; their health outcomes can be compared to those for a similar unexposed cohort (a control group).
(b) Outline factors that may affect the reliability of such cohort studies. (6)
Reliability of epidemiological cohort studies is affected by:
- inadequacy of the data - health records / death certificates are not very reliable sources of information on occupation / illness / cause of death
- inaccurate recollection of past exposures / occupational history etc
- tendency to tell researchers what they “want to hear” (“now you come to mention it…” = recall bias)
- cohort size - need reasonably large numbers to ensure statistical validity
- difficulties in selecting comparable cohorts
- confounding factors - lifestyle (smoking / diet / exercise etc); social class / income
- long latency periods for certain conditions requires long term studies - delayed results
- difficulty in tracking people / people drop out / move away
- “healthy worker effect” - sick individuals tend to be “selected out” of workforce so cohort is not representative of general population (selection bias)
(a) Outline the advantages and disadvantages of animal testing as a model to predict the effects of hazardous substances on humans. (6)
Advantages of animal testing:
similarities to human physiology, biochemistry; fewer variables / trial conditions can be more easily controlled than in human studies;
avoids risk to human study subjects /
ethically more acceptable than human trials; results available more quickly.
Disadvantages:
animal response not necessarily equivalent to human response;
doses and experimental conditions are not typical of human exposures;
ethical issues (animal rights);
animal testing to be minimised (in accordance with REACH);
time consuming / expensive; tends to focus on a single substance – does not take account of mixed exposures, lifestyle factors and synergistic effects.
(b) A principle of REACH legislation is that animal testing should only be done as a last resort.
Outline how each of the following can provide data on the human health effects of hazardous substances without animal testing:
(i) in vitro testing (3)
in vitro = in glass / test-tube / petri dish;
no living organism used;
cells / tissues extracted from
living organism cultured / grown in controlled environment;
cells / tissues exposed to test substance;
harmful effects on cells at various concentrations observed;
metabolic processes identified.
(b) A principle of REACH legislation is that animal testing should only be done as a last resort.
Outline how each of the following can provide data on the human health effects of hazardous substances without animal testing:
(ii) read-across (3)
concept that substances with similar molecular structures will have similar toxicological effects;
uses existing data available from previous trials as a means of predicting likely effects.
(b) A principle of REACH legislation is that animal testing should only be done as a last resort.
Outline how each of the following can provide data on the human health effects of hazardous substances without animal testing:
(iii) Quantitative Structure Activity Relationship (QSAR) (2)
Computer-based system that predicts likely human effects by analysis of structural relationships / similarities between chemicals - based on concept of “active groups” - to give numerical assessment
(c) A UK company manufactures 3 tonnes / year of a new hazardous substance for sale in the EU.
Outline the steps a company must take in order to comply with the REACH legislation. (6)
Manufacture within UK = REACH applies; over 1 tonne per year = requirement to register
substance with ECHA (European Chemicals Agency);
registration requires production of a technical
dossier - to include physical, chemical, toxicological / eco-toxicological properties (chemical safety report, safety assessment / exposure scenarios NOT required*);
substance must be classified and
labelled in accordance with CLP regulation ;
MSDS must be provided to users;
any changes to formulation or quantities manufactured notified to ECHA.
[* only required if manufacturing >10 tonne / year]
Human epidemiology and animal studies are methods that can be used to investigate whether a substance is carcinogenic.
(a) Outline the advantages of each of these methods. (3)
The advantages of using animal studies to investigate the possible carcinogenic effects to humans are:
• using animals avoids human exposure (and hence possible human deaths)
• laboratory animals (eg mice / rats) have a similar physiology and metabolism to humans
so give a reasonable indication of the likely effects on humans
• laboratory animals are readily available so relatively large sample sizes can be used
which gives more reliable statistical data
• the tests can be completed relatively quickly, giving faster results
• it can be argued that animal studies are more ethical than using epidemiological methods
involving humans
• animal studies are more likely to detect carcinogenic potential than in vitro testing (eg
Ames tests, which rely on evidence of cell mutation in bacteria).
Human epidemiology and animal studies are methods that can be used to investigate whether a substance is carcinogenic.
(b) Outline the disadvantages of each of these methods. (7)
The disadvantages of using animal studies to investigate the possible carcinogenic effects to humans are:
• that the dose/response effect may vary in different animal species and so extrapolating
data to humans may not always be reliable
- that conducting animal studies can be time-consuming and expensive
- ethical considerations / public opinion can make this approach more difficult to undertake
- animal tests generally involve a single substance so may not identify synergistic effects that could arise in humans exposed to other substances at the same time
(a) Explain why it is difficult to determine whether cancers in the working population are caused by exposure to substances used at work. (6)
the long latency period of many cancers, with changes in the exposure pattern and exposed population during that period;
the multi-causality of many cancers and the potential for synergism and interaction with non-occupational causes;
the prevalence of common cancers, such as lung cancer, in the general population;
individual susceptibility, and poor historical records, particularly of past exposure.
(b) Review the merits and limitations of each of the following methods for identifying the carcinogenic potential of a substance.
(i) Human epidemiology (5)
human epidemiology, whilst being a definitive method for identifying human carcinogens, is expensive and time consuming and usually requires large populations.
It is not a method to be deployed for
assessing the carcinogenic potential of new substances and suffers from problems of
sensitivity, specificity, and reliance on accurate records for assessing substances currently
in use.
(b) Review the merits and limitations of each of the following methods for identifying the carcinogenic potential of a substance.
(ii) Animal studies (5)
Animal testing studies are the best experimental method though they, too, can be expensive and time consuming but the data can be gathered more quickly than by epidemiology.
Apart from any ethical concerns, there are difficulties in extrapolating animal data to humans and often very large doses are required to produce a response which may in any case vary with different species.
(b) Review the merits and limitations of each of the following methods for identifying the carcinogenic potential of a substance.
(iii) In vitro mutagenicity testing. (4)
Finally in-vitro mutagenicity testing such as the Ames Test is rapid, low cost and avoids
ethical problems. However, whilst a finding of mutagenic potential may well also indicate
carcinogenic potential, the tests are not totally reliable and they can produce both false
positives and false negatives.
Outline, using an example, why and how a retrospective case-control study is carried out. (5)
Epidemiological methods are used to try to establish a link between exposure to a hazardous agent [cause] and cases of (work-related) ill-health [effect];
this usually involves the study of two groups
(“cohorts”) – one exposed, the other not exposed to see if there is a significant difference in the incidence of the ill-health effect between the two groups.
A retrospective cohort involves “a look back in time” often at statistical data, exposure history, occupational history etc.
For example, by studying and comparing health outcomes in both exposed
and unexposed groups / cohorts it may be possible to identify any differences that may be attributable to their exposure history.
For example by comparing illness in ex-miners who have been exposed to coal dust with illness in ex-hospital porters of similar age profile, socio-economic background etc.
it may be possible to attribute specific types of lung disease to coal dust.
Similarly epidemiological studies relating to mesothelioma were generally retrospective - people developed the disease and by
looking back at occupational history it was possible to identify causal factors.
Often applied to “outbreaks” of disease (eg legionella - track back to where people with disease have been over last 10
days)
Safety Data Sheets (SDS) provide important information to employers who are required to assess exposure to hazardous substances in their workplace.
(a) Identify FIVE types of information on a typical SDS. (5)
(b) In EACH case outline how the information could contribute to the assessment of exposure. (5)
Information included on a typical SDS will include:
(1) Name(s), chemical formula, CAS (Chemical Abstract Service) number of substance (mixture / preparation).
Contributes to assessment by helping identify nature of substance, class of chemicals it belongs to - eg organo-metallic compounds, polycyclic aromatic hydrocarbons etc;
can form basis of “chemical analogy”;
can provide useful guide to potential chemical interactions with other substances
which may be being used.
(2) Chemical and physical properties - physical, colour etc;
melting point, boiling point, vapour
pressure;
chemical composition if a mixture / preparation.
Contributes to assessment by providing
useful information on physical state (solid, liquid, gas) during use, appearance;
composition / hazardous constituents;
volatility - extent to which vapours will be generated.
(3) Hazard category and symbol eg UN Class 8, subsidiary hazard Class 6.1 = Corrosive and Toxic.
Provides clear indication of nature of hazard(s) involved and likely health effects.
(4) Exposure standards (corresponding to entries in EH40) eg WELs, BMGVs and Sk / Carc / Sen annotations - provide a basis for evaluating exposure levels and the effectiveness of existing control
measures.
Other supplementary toxicological information eg LD50 can give useful information on
relative toxicity which can be used in assessment and in developing appropriate control measures eg
ventilation.
(5) Risk phrases and safety phrases (CHIP regs) - provide useful information on nature of hazard involved, routes of entry and precautions / emergency action - eg R45 may cause cancer;
R20 Harmful by contact with skin;
R23 Toxic by inhalation;
S20 When using do not eat or drink;
S24 - avoid contact with skin;
S39 Wear eye / face protection - PPE requirements.
(6) Precautions to be adopted during transport, storage, handling and use provide useful information on PPE / RPE, ventilation and general requirements for control.
(7) Emergency information - first aid procedures, spill control action, measures for safe disposal etc.
Assists by providing useful information for assessing emergency requirements and procedures needed to comply with Reg 13 COSHH.
Comment: Some of the 16 elements of a SDS are not considered relevant to assessment of exposure - eg name & address of manufacturer;
emergency contact number.
(a) Explain why it is difficult to determine whether cancers in the working population are caused by exposure to substances at work. (6)
Difficult to determine whether cancers in the working population are caused by exposure to
substances at work because of:
• long latency periods before cancers appear - exposed individuals may have changed jobs and / or moved away meaning that the connection between exposure and cancer is more difficult
to establish
• multi-causality - few cancers can be attributed unambiguously to a specific agents
(mesothelioma, angiosarcoma) - therefore difficult to make link with certainty (instead a
statistical probability is applied)
- many cancers are common in the general population (eg lung cancer) so there is often no obvious link / clear pattern relating to occupational exposure
- cancer can be caused by a combination of social, environmental and occupational exposures interaction / synergism / potentiation (eg asbestos + smoking)
- poor historical records - death certificates, morbidity / mortality data;
occupational history
• individual susceptibility / genetic vulnerability
(b) Review the merits and limitations of each of the following methods for Identifying the carcinogenic
potential of a substance.
(i) Human epidemiology (5)
Human epidemiology
MERITS
• involves the application of established
methodologies
• techniques are validated, statistically-based & directly applicable to human exposures
• identify patterns of ill-health and potential
causal relationships
LIMITATIONS
• Requires large populations / cohorts for analysis
- need to track cohorts over long periods
• Resource intensive / time-consuming (delayed results) and requires high levels of expertise
• Results can be inconclusive - difficulty in
screening out confounding factors - social /
environmental / lifestyle / age / gender etc
• Reliability of data is questionable (medical
records, death certificates, recall etc)
(b) Review the merits and limitations of each of the following methods for Identifying the carcinogenic
potential of a substance.
(ii) Animal studies
MERITS
• Avoids human exposures
• Results produced more quickly than above
• Certain species provide a good analogy for
human exposures
• No complications of tracking cohort etc
LIMITATIONS
• Results may not reflect human response to
similar exposures (2-napthylamine = bladder
cancer in humans not in rats)
- Animal studies tend to focus on acute effects - human cancers often involve chronic effects
- Animal studies are “artificial” and do not reflect the complexity of human exposures - diet / smoking etc
- Ethical objections to animal testing
(b) Review the merits and limitations of each of the following methods for Identifying the carcinogenic potential of a substance.
(iii) In vitro mutagenicity testing
MERITS
- Ames test = widely used / validated / recognised methodology
- Quick and inexpensive
- No ethical issues
- Can form preliminary basis for further in vivo testing
• Can help identify mutagenic / carcinogenic
mechanisms
LIMITATIONS
• Results not always relevant to human exposures
• Not all mutagens are carcinogens(= false
positives)
• Results from Ames test may be unreliable - false positives / false negatives
(a) State the purpose of, and Identify the duty holders under, the Chemicals (Hazard Information and Packaging for Supply) Regulations 2002 ( CHIP) (3)
The purpose of the CHIP regulations is to protect people and the environment by ensuring that hazardous substances are:
- properly classified (identified) in terms of their hazardous properties
- accompanied by appropriate hazard information (labels and safety data sheets)
• suitably packaged to reduce the likelihood of loss of containment, tampering etc
The CHIP regs place duties on suppliers of hazardous substances.
‘Supply’ means making a chemical
available to another person. Manufacturers, importers, distributors, wholesalers and retailers are all examples of suppliers.
(b) Outline the specific measures that a duty holder under CHIP must take to comply with these
regulations. (7)
Suppliers must classify hazardous substances / preparations in accordance with the requirements of the Approved Methods for the Classification of Hazardous Substances and the corresponding entries in the Approved Supply List.
This involves identifying the substances in terms of their physico-chemical properties and allocating them to one of the relevant hazard categories – toxic, corrosive,
irritant, harmful, carcinogenic, mutagenic, teratogenic etc.
Hazard information must include suitable labelling / SDS to include:
- the name, address, phone number of the supplier / manufacturer
- the appropriate hazard warning symbol
- details of the physical and chemical properties of the substance / preparation
- emergency information - first-aid, spill control
- risk phrases - R45 - may cause cancer
- safety phrases - S24 - avoid contact with skin
- disposal information
Hazardous substances / preparations must be packaged in accordance with to UN type-approved packaging standards which include features such as impact resistance for receptacles, child-proof openings, tactile warnings / information for products which are supplied to the public.
The table below shows data provided in a supplier’s catalogue for three different grades of the same industrial chemical.
Product code. AS1/01.
Description. Fine white powder
Average particle size (microns). 15
Particle size disribution. 12-20
Product code. AS1/02.
Description. Fine white powder
Average particle size (microns). 8
Particle size disribution. 7-10
Product code. AS1/03.
Description. Fine white powder
Average particle size (microns). 2
Particle size disribution. 1-5
(a) Use the data to identify the likely distribution in the respiratory tract of each of these powders following inhalation.(3)
(b) In each case describe the mechanisms the body may use to defend itself. (7)
(a) + (b)
AS1/01 - Particle size indicates that the dust will lodge in nasal hair and upper respiratory tract - removed by sneezing, coughing, mucous, swallowing
AS1/02 - Particle size indicates that the dust will deposit in the “thoracic” area - trachea, bronchi, bronchioles - removable via ciliary escalator, mucous etc
AS1/03 - Particle size indicates that the respirable dust will penetrate to the gas-exchange regions of the lung (alveoli) where it may pass across cell membrane into blood stream or deposit initiating an auto-immune response whereby the dust particles are engulfed by phagocytes which may cause scarring / fibrosis / pneumoconiosis (dependent on physico-chemical properties of the dust).
(a) Explain the meaning of the term ‘carcinogen’. (2)
A ‘carcinogen’ is an agent that causes cancer; has the ability to produce malignant
tumours, attacks cell reproduction mechanisms;
causes changes in cell’s DNA
resulting in abnormal cells and uncontrollable growth; and produces effects that are
irreversible and continue well after the initial exposure.
(b) Outline the role of Workplace Exposure Limits (WELs) when deciding if exposure to a carcinogen is ‘adequately controlled’ for
the purposes of the Control of Substances Hazardous to Health (COSHH) Regulations 2002. (2)
exposure to a carcinogen is adequately controlled when a WEL, if one exists, is not exceeded and when exposure
is reduced to the lowest level that is reasonably practicable.
(c) Under COSHH exposure to substances hazardous to health (including carcinogens) shall only be treated as adequate if the
‘principles of good practice’ are applied.
Outline SIX of these principles. (6)
Examples of the principles include those dealing with design and operation of the processes and activities to minimise emission;
the need to control exposure by measures that are proportionate to the health risk;
the choice of the most
effective and reliable control options which minimise the escape and spread of the
substances hazardous to health;
the need to take into account all relevant routes of exposure not just inhalation;
the need for the periodic checking and review of control measures to ensure their continuing effectiveness;
the provision of suitable personal
protective equipment when adequate control of exposure cannot be completely
achieved by other means;
the provision of information and training to employees on the hazards and risks from the substances they use in their work and the use of the control measures that have been introduced to minimise the risks;
and
the need to ensure that the introduction of the selected control measures does not increase the overall risk to health and safety.
