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Principper for sundhedsmæssig vurdering af kemiske stoffer med henblik på fastsættelse af kvalitetskriterier for luft, jord og vand
English Summary
In Denmark, health based quality criteria are set for chemical substances in soil, drinking water and ambient air according to the principles laid down in the Guideline [1] for health based evaluation of
chemical substances in drinking water and in Appendix A of the Industrial Air Pollution Control Guidelines [2]. These principles are currently undergoing a revision based on the experiences gained during the
last ten years within this area as well as on the improved knowledge internationally regarding the various steps in the risk assessment process. The aim of this report is to update the current knowledge and
experiences in order to provide the basis for the revision of the principles for the setting of health based quality criteria for chemical substances in soil, drinking water and ambient air. The most essential
features of the principles are summarised below.
The report has been prepared for the Danish Environmental Protection Agency (DEPA) by the Institute of Food Safety and Nutrition, Danish Veterinary and Food Administration.
The scientific basis for the assessment of health based quality criteria for chemical substances in soil, drinking water and ambient air, below referred to as `quality criteria', consists of a hazard identification, a
dose (concentration) – response (effects) assessment (hazard characterisation), and an exposure assessment.
The hazard identification and characterisation are based on data elucidating the toxicological effects in humans and experimental animals of a given chemical substance. Data are collected from national and
international criteria documents and monographs, by searching in international databases, and from original scientific literature. Furthermore, unpublished data from the risk assessment reports within the EU
programme on the evaluation and control of existing substances are also included in the hazard assessment and occasionally unpublished data from industry or other sources.
Human data include information from case reports (e.g., poisonings), clinical examinations, studies on volunteers, experiences from the working environment, and epidemiological studies. For most chemical
substances however, human data are not adequate or available. Therefore, the quality criteria for chemical substances in soil, drinking water and ambient air are primarily based upon data from studies in
experimental animals. Ideally, a complete database including information on toxicokinetics, acute toxicity, irritation, sensitisation, repeated dose toxicity, mutagenicity and genotoxicity, carcinogenicity, and
toxicity to reproduction should be available. In relation to the setting of quality criteria for chemical substances in soil, drinking water and ambient air, this requirement is most often not fulfilled. According to
the current administrative practice of the DEPA, the quality criteria are based on the existing database and to compensate for the inadequacy of the database, an uncertainty factor is applied.
Exposure to a chemical substance can result in a broad spectrum of effects varying from mild effects as e.g., irritation to fatal poisonings. The type and severity of the effects observed is most often correlated
with the exposure concentration. The first step in the hazard assessment is the hazard identification, i.e., an identification of the toxicological effects, which a substance has an inherent capacity to cause. The
next step is the hazard characterisation, i.e., estimation of the relationship between dose or exposure concentration to a substance, and the incidence and severity of an effect. Regarding the severity of a given
effect, it is evaluated whether the effect can be considered as being adverse or not. Generally, an effect is considered as being adverse when there is a change in morphology, physiology, functional capacity,
development, and/or life span in the exposed individuals, and when the incidence of the effect is statistically significantly different from that in the control group. The hazard assessment also includes an
evaluation of the `no observed adverse effect level' (NOAEL) and `the lowest observed adverse effect level' (LOAEL) for the various effects observed.
When all the relevant toxicological data have been evaluated, the hazard(s) considered most important, “the critical effect(s)”, is identified, i.e., the effect(s), which is considered as being the essential one for
the setting of the quality criteria. The critical effect(s) can be considered to be of two types: those considered to have a threshold and those for which there is considered to be some risk at any level
(non-threshold, e.g. genotoxic carcinogens). For threshold effects, a NOAEL (or LOAEL) is identified for the critical effect. In relation to the setting of quality criteria for chemical substances in soil, drinking
water and ambient air, effects are generally considered to be of more concern the lower the concentration (or dose) at which they occur, and the effect observed at the lowest concentration (or dose level)
often forms the basis for the quality criteria.
The next step in the setting of quality criteria for chemical substances in soil, drinking water and ambient air is the derivation of the tolerable daily intake (TDI), which is an estimate of the intake of a
substance, which can occur over a lifetime without appreciable health risk. For acutely toxic substances, the maximal tolerable dose or concentration (MTD/K) forms the basis for the quality criteria. The
derivation of the TDI depends on the type of the critical effect: threshold or non-threshold.
For threshold effects, the TDI is calculated by dividing the NOAEL (or LOAEL) for the critical effect(s) with an uncertainty factor (UF). The current practice according to the DEPA in relation to the setting
of quality criteria for chemical substances in soil, drinking water and ambient air is to divide the UF into three categories (UFI, UFII, UFIII).
UFI accounts for the interspecies variation in susceptibility, i.e., accounts for that humans may be more susceptible to a given effect than experimental animals. According to the current practice of the DEPA
in relation to the setting of quality criteria for chemical substances in soil, drinking water and ambient air, a default value of 10 is used for UFI. The interspecies differences can be divided into differences in
metabolic size and remaining species-specific differences. To account for differences in metabolic size, three methods are used in practice: extrapolation based on 1) body weight, 2) surface area, and 3)
caloric demand. Scaling on the basis of caloric demand to adjust oral NOAELs for metabolic size is internationally considered as being more appropriate compared to extrapolation based on body weight.
The data on the remaining (i.e., after metabolic scaling) uncertainty in the extrapolation from animals to humans are too limited in order to suggest a default value. A number of analyses [3] have been
performed in order to propose a default value to account for interspecies differences (metabolic as well as the remaining species-specific differences). These analyses support to continue to use a default
value of 10 for UFI in relation to the setting of quality criteria for chemical substances in soil, drinking water and ambient air when correction for metabolic size is based on body weight.
UFII accounts for the differences in interindividual susceptibility, i.e., accounts for subgroups in the population such as children and the unborn child, pregnant women, elderly, or sick people may be more
susceptible than the general population. According to the current practice of the DEPA in relation to the setting of quality criteria for chemical substances in soil, drinking water and ambient air, a default value
of 10 is used for UFII. The responses of humans to xenobiotics may vary because of a number of biological factors, such as age, sex, genetic composition, health status, and lifestyle, and reflect both
differences in toxicokinetics and in toxicodynamics. A number of analyses [4] have been performed in order to propose a default value to account for the interindividual differences. These analyses support to
continue to use a default value of 10 for UFII in relation to the setting of quality criteria for chemical substances in soil, drinking water and ambient air.
UFIII accounts for the quality and relevance of the data, i.e., accounts for the uncertainties in the establishment of a NOAEL for the critical effect. According to the current practice of the DEPA in relation to
the setting of quality criteria for chemical substances in soil, drinking water and ambient air, a value from 1 to 100 is used for UFIII. The UFIII includes elements such as the 1) quality of the database, e.g.,
data on specific toxic endpoints are lacking or inadequate; 2) route-to-route extrapolation, e.g., no studies using the appropriate exposure route are available; 3) LOAEL-to-NOAEL extrapolation, e.g., a
NOAEL cannot be established for the critical effect; 4) subchronic-to-chronic extrapolation, e.g., no chronic studies on which to establish the NOAEL are available; and 5) nature and severity of toxicity,
e.g., the critical effect is toxicity to reproduction, carcinogenicity or sensitisation. A number of analyses4 have been performed in order to propose a default value to account for the various elements of UFIII.
Based on these analyses, a default value for UFIII as well as for the various elements of UFIII cannot be suggested. In relation to the setting of quality criteria for chemical substances in soil, drinking water
and ambient air it is therefore recommended to evaluate the value of the UFIII case-by-case based on expert judgement.
Finally, the total UF has to be reviewed. If the magnitude of the total UF is very high (e.g., above 10000), the database might be considered as too limited in order to set a health based quality criteria for a
given chemical substances in soil, drinking water and ambient air.
For non-threshold effects (e.g., genotoxic carcinogens), there is no clear consensus on appropriate methodology for the calculation of the TDI. A number of approaches based largely on characterisation of
dose response analyses and low-dose extrapolation have been adopted for assessment of such effects, which all require administrative/political judgements of acceptable health risk.
A number of mathematical models have been developed for extrapolation from responses at the high experimental doses generally used in animal carcinogenicity tests to those of the substantially lower
exposure levels encountered in human situations. The most extensively used mathematical model to date is the Linearised Multi-Stage (LMS) model, which has been used by US-EPA and by WHO in
relation to guidelines for drinking water quality. Another model is the One-hit model, which according to the current practice of the DEPA is used in relation to the setting of quality criteria for genotoxic
carcinogens in soil, drinking water and ambient air. US-EPA has recently published (1996, 1999) [5] proposed guidelines for carcinogen risk assessment and one of the key issues is to use linear
extrapolation downwards from a benchmark dose (LED10, the 95% lower confidence limit on a dose associated with 10% extra tumour risk adjusted for background) in cases where there is no evidence
for non-linearity in the dose response. Within the EU, it has recently been proposed to use the dose descriptor T25 from animal studies as a basis for the quantitative risk characterisation for carcinogens [6].
T25 is defined as the chronic dose rate (in mg/kg b.w./day), which will give 25% of the animals tumours at a specific tissue site, after correction for spontaneous incidence, within the standard lifetime of that
species. The results obtained with the T25-approach, which can be calculated without computer programmes, are in agreement with results from computer-based extrapolation methods such as the
LMS-model and the benchmark method using LED10. Based on the current knowledge and experiences, it is recommended in relation to the setting of quality criteria for chemical substances in soil, drinking
water and ambient air either to continue to use the One-hit model or alternatively, to implement the T25-approach.
There are no regulations on acceptable health risk, but there is an administrative practice followed by various authorities. Generally, a lifetime risk between 10-6 and 10-7 is considered a tolerable level. A
lifetime risk of 10-6 for developing tumours means that exposure for life time to a specific dose or concentration may result in that one individual of a million of exposed individuals develops one tumour. The
current administrative practice according to the DEPA in relation to the setting of health based quality criteria for genotoxic carcinogens in soil, drinking water and ambient air is to use a lifetime risk of 10-6.
The general population is exposed to chemical substances via inhalation of vapours, aerosols and dust in the air (indoor air as well as ambient air), intake of food, drinking water and soil, and dermal contact
to water, soil and consumer products. The exposure assessment generally estimates the concentrations/doses to which human populations are or may be exposed. According to the current practice of the
DEPA in relation to the setting of quality criteria for chemical substances in soil, drinking water and ambient air, no such straightforward exposure assessment is performed, but standard exposure rates for
soil, drinking water, and air are used.
The exposure concentration in the air (expressed in mg/m³) can be converted to an average daily dose (expressed as mg/kg b.w./day) by using the body weight and the daily average inhalation rate
(ventilation rate VR, expressed as m³/day). Breathing rates are affected by numerous individual characteristics, including age, gender, body weight, health status, and levels of activity. According to the
current practice of the DEPA in relation to the setting of health based quality criteria for chemical substances in ambient air, a standard inhalation rate of 20 m³/day (daily average for adults) is used. A
number of analyses on inhalation rates have been performed during the last 10 years, predominantly in the USA. Based on selected key inhalation rate studies, US-EPA [7] has recommended a daily average
inhalation rate (VR) for long-term exposure of 11.3 m³/day for women and of 15.2 m³/day for men (Table 6.1.1B); an upper percentile has not been recommended. The recommended inhalation rates for
men and women are different than the 20 m³/day, which has commonly been assumed in the past US-EPA risk assessments. For children, US-EPA7 has recommended various age-specific inhalation rates
(Table 6.1.1B). Recommended inhalation rates have also been given children and adults for short-term exposures in which distribution of activity patterns are specified (Table 6.1.1B).
The exposure concentration in soil (expressed in mg/kg soil) can be converted to an average daily dose (expressed as mg/kg b.w./day) by using the body weight and the average daily soil intake (expressed
as mg/day). The potential for exposure to chemical substances via this source is greater for children because they are more likely to ingest more soil than adults as a result of behavioural patterns present
during childhood such as the mouthing of objects or hands. Deliberate soil ingestion is defined as pica. According to the current practice of the DEPA in relation to the setting of health based quality criteria
for chemical substances in soil, a standard estimate for soil intake of 200 mg/day (daily average for an infant) is used with an intake of 10 g for acutely toxic substances in relation to pica. A number of
analyses on soil intake among children have been performed during the last 10 years, predominantly in the USA. Based on selected key studies on soil intake among children, US-EPA [8] has recommended
a daily average of 100 mg/day for soil intake among children under 6 years of age with an upper percentile (95 percentile) of 400 mg/day (Table 6.1.2.1C). For children who deliberately ingest soil, an intake
of 10 g/day has been recommended by US-EPA8 as a reasonable value for use in acute exposure assessments. Adults may also ingest soil or dust particles that adhere to food, cigarettes, or their hands.
According to US-EPA8, only three studies have attempted to estimate adult soil ingestion; a daily average of 50 mg/day for adult soil ingestion has been recommended (Table 6.1.2.1C).
The general population can also be exposed to chemical substances in soil by dermal contact, e.g., via outdoor recreation, gardening, construction, and playing. No data are available regarding a daily
average for dermal contact to soil. According to the current practice of the DEPA in relation to the setting of health based quality criteria for chemical substances in soil, a standard estimate for dermal
contact to soil of 1 g/day is used for children (daily average) and of 0.1 g/day for adults (daily average).
The exposure concentration in drinking water (expressed in mg/litre) can be converted to an average daily dose (expressed as mg/kg b.w./day) by using the body weight and the average daily drinking water
intake (expressed as litre/day). The daily consumption of drinking water varies with age, levels of physical activity, and fluctuations in temperature and humidity. According to the current practice of the
DEPA in relation to the setting of health based quality criteria for chemical substances in drinking water, a standard estimate for drinking water intake of 2 litres/day (daily average for an adult) is used. A
number of analyses on drinking water intake have been performed during the last 10 years, predominantly in the USA. Based on selected key studies on drinking water intake, US-EPA8 has recommended
a daily average of 1.4 litre/day for drinking water intake among adults (age: above 19 years) with an upper percentile (90 percentile) of 2.3 litres/day (Table 6.1.3D). These recommended values are different
than the 2 litres/day commonly assumed in US-EPA risk assessments. For children, US-EPA8 has recommended various age-specific drinking water intake rates (Table 6.1.3C).
Finally, the health based quality criteria for chemical substances in soil, drinking water and ambient air are derived for the relevant media by dividing the TDI with the standard exposure rate of this media. To
ensure that the total daily intake of a given chemical substance from the various media does not exceed the TDI, a certain percentage of the TDI can be assigned to the relevant media (allocation) and in this
way account for other important exposure routes such as exposure through the food.
The health based quality criteria derived as described above are used as the basis for the setting of quality criteria for chemical substances in soil and drinking water, and of C-values [9] in ambient air. In this
step, other than health based viewpoints may be taken into account, including aesthetical factors such as odour (all media), discoloration (soil, drinking water), taste (drinking water), and microbial growth
(drinking water). The C-value is fixed as a mean hourly value that must not be exceeded by more than about seven hours a month, i.e., 1% of the time. When implementing health based quality criteria in air
to C-values, the nature of the toxicological effects and the period during which the substances remain active are of crucial importance. Four different categories have been established, for further details are
referred to the Appendix A of the Industrial Air Pollution Control Guidelines [10]. Furthermore, economic or political administrative factors may also be taken into account in relation to the setting of quality
criteria for chemical substances in soil, drinking water, and ambient air.
Fodnoter
[1] Sundhedsmæssig vurdering af kemiske stoffer i drikkevand. Vejledning fra Miljøstyrelsen Nr. 1 1992, Miljøministeriet, Miljøstyrelsen.
[2] Industrial Air Pollution Control Guidelines. Vejledning fra Miljøstyrelsen Nr. 9 1992, Ministry of the Environment, Denmark, Danish Environmental Protection Agency.
[3] For references, see section 4.6.
[4] For references, see section 4.6.
[5] For references, see section 5.5.
[6] For references, see section 5.5.
[7] US-EPA (1997). Exposure Factors Handbook EPA/600/P-95/002Fa. Update to Exposure Factors Handbook EPA/600/8-89/043 - May 1989. http://www.epa.gov/nceawww1/pdfs/efh/front.pdf
[8] US-EPA (1997). Exposure Factors Handbook EPA/600/P-95/002Fa. Update to Exposure Factors Handbook EPA/600/8-89/043 - May 1989. http://www.epa.gov/nceawww1/pdfs/efh/front.pdf
[9] Contribution value. Defined as the maximum amount of any pollutant a company is allowed to emit in the air as immission. The C-value is used in the calculations for all chimneys that emit pollutants into
the atmosphere.
[10] Industrial Air Pollution Control Guidelines. Vejledning fra Miljøstyrelsen Nr. 9 1992, Ministry of the Environment, Denmark, Danish Environmental Protection Agency.
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Version 1.0 Januar 2005, © Miljøstyrelsen.
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