Working document for the Expert Review Panel




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Working group on HD DNEL/DMEL derivation


Working document for the Expert Review Panel
Adapted by comments received
To be finalised by June 2008


by
Gerard Swaen & Chris Money

(ECETOC)


and

Sandra Bausch & Dinant Kroese

(TNO)
Introductory note

Background
Although HD are routinely used in many standard setting processes e.g. for the derivation of EU Indicative Limit Values, the process by which HD are assessed and subsequently used in these has not been explicitly described. In order to provide the necessary clarity to the REACH TGD, therefore, TNO and ECETOC have worked to identify suitable sources of information which can provide suitable guidance to support each of the steps.

Following the ECETOC/TNO workshop in November 2007 and the Competent Authorities discussions on RIPs 3.2 and 3.3 (culminating in the adoption by the CAs of the consolidated 3.2/3.3 TGD in March 2008), TNO and ECETOC have worked to incorporate the sentiments expressed by participants at the November workshop with the general structure and contents of the guidance to be adopted (and especially those parts relevant for setting DNELs and DMELs). These are contained in the present document. This document is not thoroughly checked for spelling, internal consistency, and overlap/provided with cross referencing etc.


Views Sought
With these considerations in mind, your comments are sought on the following issues captured within the guidance:

  • Evaluation of the quality of human data independently from animal studies but in a manner that parallels the criteria used to categorise animal data;

  • Comparison of the human and animal data to determine which data source is likely to be most suitable for establishing the DNEL (or DMEL) not by using strict weight of evidence criteria, but rather, a transparent process building off the IPCS human relevance framework data;

  • Differentiation only on the basis of short term and/or chronic effects, not addressing separate human endpoints;

  • Proposal of a set of Assessment Factors that are judged to be appropriate for human data, based upon experience from related areas of limit setting e.g. workplace exposures, food standards, air quality values, etc.;

  • Deriviation of DMELs for non-threshold carcinogens using HD;

With regard to the not yet incorporated scheme (i.e. into the guidance) as depicted on page 4 of this document, yet without a narrative to be developed – if requested: is the scheme understandable, does it support the processes described in Appendix R.8-15, and thus presents added value?



Proposed process
We would welcome all your comments and suggestion by May 15th at the latest. We will then evaluate your comments and probably arrange a conference call to discuss and settle the most important issues identified. Depending on the time available before delivery to ECHA we will then circulate a second version for your review.




Part I
Below text is from the Reference TGD prepared for CA endorsement, scheduled for end March 2008.

It consists of two parts:

A. General introduction (from R4.1 & 4.3)

B. Endpoint-specific guidance (from subsections 3, 4, and 5 of R7.2 to R7.7)


Blue text is newly inserted as compared to the text presented at the Brussels 2007 Workshop

A. General introduction

4.1 Relevance of information


Human data is in principle the most relevant source of information on human toxicity. Since there may be limitations with regard to the reliability of these studies, they are normally considered together with animal, in vitro and other information in order to be able to reach a conclusion about the relevance of the effects to humans.

4.3.3 Adequacy of information


The evaluation and use of information derived from studies in humans usually requires more elaborate and in-depth critical assessment of the reliability than animal data (WHO, 1983). Four major types of human data may be submitted (1) analytical epidemiology studies on exposed populations, (2) descriptive or correlation epidemiology studies, (3) case reports and (4) in very rare, justified cases controlled studies in human volunteers.

Analytical epidemiology studies (1) are useful for identifying a relationship between human exposure and effects such as biological effect markers, early signs of chronic effects, disease occurrence, or mortality and may provide the best data for risk assessment. Study designs include:



  • Case-control (case-referent) studies, where a group of individuals with (cases) and without (controls/referents) a particular effect are identified and compared to determine differences in exposure in the recent or more distant past;

  • Cohort studies, where groups of variously exposed and non-exposed individuals are identified and differences between the groups in effect occurrence over time are studied;

  • Cross-sectional studies, where a population (e.g. a workforce) is studied, so that morbidity at a given point in time can be assessed in relation to concurrent exposure.

The strength of the epidemiological evidence for specific health effects depends, among other things, on the type of analyses and on the magnitude and specificity of the response. Confidence in the findings is increased when comparable results are obtained in several independent studies on populations exposed to the same agent under different conditions. In general, cohort studies provide stronger evidence than case-control studies, because exposure is assessed independently of the health status or outcome of the subjects in the study. Other characteristics that support a causal association are presence of a dose-response association, a consistent relationship in time and (biological) plausibility.

Criteria for assessing the adequacy of epidemiology studies include the proper selection and characterisation of the case and control groups (in case-control studies), adequate characterisation of exposure, sufficient length of follow-up for disease occurrence (in cohort studies), valid ascertainment of effect, proper consideration of biases and confounding factors. Assessment of adequacy of the studies should be conducted by epidemiologists by training.

Due to both uncertainties in epidemiological studies and true variability in the association between exposure and health outcomes within and among human populations, the available body of epidemiological evidence should be systematically reviewed and, if possible, combined. A Weight of Evidence approach is essential for risk assessment based on epidemiological data to (a) assess (sources of) heterogeneity across the studies and (b) increase statistical stability of the risk estimates. The best option to combine and summarise epidemiological data is a pooled analysis of the original data sets of the contributing studies. A meta-analysis based on published study results is a good, but somewhat more restricted alternative.

A comprehensive guidance of both the evaluation and use of epidemiological evidence for risk assessment purposes is provided by Kryzanowski et al (WHO 2000).

Descriptive epidemiology studies (2) examine differences in disease rates among human populations in relation to age, gender, race, and differences in temporal or environmental conditions. These studies are useful for identifying areas for further research but are not very useful for risk assessment. Typically these studies can only identify patterns or trends in disease occurrence over time or in different geographical locations but cannot ascertain the causal agent or degree of human exposure.

Case reports (3) describe a particular health condition in an individual or a group of individuals who were exposed to a substance. They may be particularly relevant when they demonstrate effects which cannot be observed in experimental animal studies. In many such studies, information is lacking on critical aspects such as substance identity and purity, exposure, health status of the persons exposed and even the symptoms reported; thorough assessment of the reliability and relevance of case reports is therefore necessary. Case reports also trigger analytical studies.

When they are already available, well-conducted controlled human exposure studies (4) in volunteers, including low exposure toxicokinetics studies, can also be used in risk assessment. However, few human experimental toxicity studies are available due to the practical and ethical considerations involved in deliberate exposure of individuals. Such studies, e.g. studies carried out for the authorisation of a medical product, have to be conducted in line with the World Medical Association Declaration of Helsinki, which describes the general ethical principles for medical research involving human subjects (World Medical Association, 2000).

Criteria for a well-designed experimental study include the use of a double-blind study design, inclusion of a randomised control group, sufficient duration of exposure and an adequate number of subjects to detect an effect. A meta-analysis of available similar, even small, studies is a good option.

It is emphasised that testing with human volunteers is strongly discouraged, but when there are good quality data already available they should be used as appropriate, in well justified cases.


B. Endpoint-specific guidance

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