- Email: [email protected]
Biomarkers are of little practical value in cancer epidemiology (against)
2
Debate 2
cific ionic xenobiotic transporter superfamily" will provide potential tools to assess mechanisms of many nephrotoxicants including drugs and xenobiotics, and contribute also to inventing new drugs without undesirable effects to the kidney.
~
HEALTHYVOLUNTEER STUDIESIN TOXICOLOGY
r. de Vries. National Poisons Control Centre. National Institute ofPublic Health and the Environment. PO Box 1. 3720 BA Bilthoven, The Netherlands
contribute to a "weight of evidence" approach that will improve the assessment of carcinogenic risk to humans. In addition, these transgenic mouse studies take only 6 months and require the use of less animals with less advanced cancer endpoints. This means that transgenic models are not only less on the critical path of drug development and less expensive but that they also improve animal welfare (reduction and refinement).
1. Meulenbelt *, Tj.T. Mensinga , 1.M. Kortboyer,
Introduction: The general expectation is that the demand for volunteer studies for the risk-assessment of consumer and chemical products will increase in the near future . The first reason is that the new legislation and guidelines for these products will be more restrictive concerning safety aspects. Secondly, there is a strong international tendency to decrease the number of animals used for experimental studies. Thirdly, the general public is more up-to-date informed and demanding than in the past concerning safety aspects of consumer and chemical products . The necessity of volunteer studies: For the majority of non-pharmaceutical s there are limited data on human metabolism and toxicity. The results of in-vitro and animal studies are not always interpretable for the human situation in a straight forward manner. The dose-effect or dose-response relation for a given substance might be quite different for humans. Humans may even be more susceptible than any of the animal species. Some effects, such as diplopia, dizziness, headache and nausea can only be evaluated in volunteer studies. A further advantage of the results of human studies is that there is no need to perform a 'translation' to the human situation as it is with the results of animal studies. In order to develop adequate physiological based biokinetic and biodynam ic models for human risk-assessment the results of volunteer studies can be used to fiII in the gaps of knowledge which cannot be solved with in-vitro or animal studies . Beside the above mentioned aspects, several other issues of performing volunteer studies will be highlighted , such as ethical aspects, advantages, disadvantages, expectations, and development s. Conclusions: For human risk assessment, it is recommended to gear to one another the study designs of in-vitro and animal studies 0 11 the one hand and volunteer studies on the other hand 10 improve the comparability of study results. and to gain harmonized and optimum results in the most economic way.
TRANSGENIC ANIMAL MODELSARE AN APPROPRIATE ALTERNATIVE TO THE SECOND SPECIESIN TESTING FOR CARCINOGENICITY OF PHARMACEUTICALS (FOR)
J.r. Goodman. Department of Pharmacology and Toxicology, Michigan State University, East Lansing. MI. USA Transgenic animals provide excellent research tools and they can be used now to help prioritize chemicals for carcinogenicity testing. However. at the present time, it is not appropriate to make regulatory decisions based on transgenic animal bioassays because we do not have the sufficient knowledge base that is required in order to make informed decisions. Specifically, we lack adequate confidence in a negative response, (e.g., Will a negative 24-week test be superceded if it is repeated for 36 weeks and yields a positive response?) and we do not have the ability to place a positive response into proper perspective (e.g., Will a transgenic mouse carcinogen quickly be referred to as a rodent carcinogen then a probable human carcinogen?). This presentation will focus on a critical, constructive analysis of proposed alternatives (e.g., the TG.AC, Hras2 and p53 +/ - ) with an emphasis on understanding the molecular basis of the models and juxtaposing this with our current view of carcinogenesis. I am in favor of change and I believe that transgenic animals may, eventually, aid in improving carcinogenicity testing. However, more hypothesis-driven research leading to a better understanding of the proposed models is required in order to be in a position to make sound regulatory decisions. Furthermore , it should be emphasized that our goal is not to create situations where we simply label more chemicals as rodent carcinogens. In this context. it is important to reiterate the necessity of concentrating on the basic issues: dose selection (including rational criteria for selecting the high dose ), shape of the dose-response curve (including the existence of thresholds), and species to species extrapolat ion.
D2. Debate2
Debates
I02/1 [ BIOMARKERSARE OF LITTLE PRACTICALVALUE IN CANCEREPIDEMIOLOGY (AGAINSn
Dl. Debate 1
I01/1 [
TRANSGENIC ANIMAL MODELS ARE AN APPROPRIATE ALTERNATIVE TO THE SECONDSPECIESIN TESTING FOR CARCINOGENICITY OF PHARMACEUTICALS (FOR)
H. Van Cauteren. Janssen Research Foundation. B-2340 Beerse,
Belgium As specified in the ICH process . a survey of six pharmaceutical data bases revealed that the use of one species (rats or mice) in two-year testing would not result in loss of information on carcinogenicity relevant to human risk assessment for human pharmaceuticals. The conduct of only one two-year study will allow investment in other, shorter-term models such as those using transgenic mice. This conduct will mean not only an investment in future models. but, as such, the results obtained from these transgenic mouse models will
S.R. Tannenbaum. Massachusetts Institute of Technlogy,
Cambridge. MA. USA The types of biomarkers used in cancer epidemiology include biomarkers of: internal dose of carcinogens, biological effects of carcinogen exposure, precancerous lesions, and cancer. The utility of any biomarker is related to its prior validation in separate studies and its appropriate application in well-designed epidemiological investigations. This side of the debate will be confined to biomarkers of internal dose in relation to disease outcome. The rules of causality in epidemiological studies must be applied, particularly those of biological plausability and temporali ty. The rules of analytical chemistry also apply, particularly those of accuracy. precision, and chemical identity. It will be demonstrated through specific cases that when the rules are followed biomarkers may be of great value for the study of metabolic polymorphisms, identification of cryptic exposures, association of exposures with risk of cancer, and for prudent public health decisions.
Debate 2
cific ionic xenobiotic transporter superfamily" will provide potential tools to assess mechanisms of many nephrotoxicants including drugs and xenobiotics, and contribute also to inventing new drugs without undesirable effects to the kidney.
~
HEALTHYVOLUNTEER STUDIESIN TOXICOLOGY
r. de Vries. National Poisons Control Centre. National Institute ofPublic Health and the Environment. PO Box 1. 3720 BA Bilthoven, The Netherlands
contribute to a "weight of evidence" approach that will improve the assessment of carcinogenic risk to humans. In addition, these transgenic mouse studies take only 6 months and require the use of less animals with less advanced cancer endpoints. This means that transgenic models are not only less on the critical path of drug development and less expensive but that they also improve animal welfare (reduction and refinement).
1. Meulenbelt *, Tj.T. Mensinga , 1.M. Kortboyer,
Introduction: The general expectation is that the demand for volunteer studies for the risk-assessment of consumer and chemical products will increase in the near future . The first reason is that the new legislation and guidelines for these products will be more restrictive concerning safety aspects. Secondly, there is a strong international tendency to decrease the number of animals used for experimental studies. Thirdly, the general public is more up-to-date informed and demanding than in the past concerning safety aspects of consumer and chemical products . The necessity of volunteer studies: For the majority of non-pharmaceutical s there are limited data on human metabolism and toxicity. The results of in-vitro and animal studies are not always interpretable for the human situation in a straight forward manner. The dose-effect or dose-response relation for a given substance might be quite different for humans. Humans may even be more susceptible than any of the animal species. Some effects, such as diplopia, dizziness, headache and nausea can only be evaluated in volunteer studies. A further advantage of the results of human studies is that there is no need to perform a 'translation' to the human situation as it is with the results of animal studies. In order to develop adequate physiological based biokinetic and biodynam ic models for human risk-assessment the results of volunteer studies can be used to fiII in the gaps of knowledge which cannot be solved with in-vitro or animal studies . Beside the above mentioned aspects, several other issues of performing volunteer studies will be highlighted , such as ethical aspects, advantages, disadvantages, expectations, and development s. Conclusions: For human risk assessment, it is recommended to gear to one another the study designs of in-vitro and animal studies 0 11 the one hand and volunteer studies on the other hand 10 improve the comparability of study results. and to gain harmonized and optimum results in the most economic way.
TRANSGENIC ANIMAL MODELSARE AN APPROPRIATE ALTERNATIVE TO THE SECOND SPECIESIN TESTING FOR CARCINOGENICITY OF PHARMACEUTICALS (FOR)
J.r. Goodman. Department of Pharmacology and Toxicology, Michigan State University, East Lansing. MI. USA Transgenic animals provide excellent research tools and they can be used now to help prioritize chemicals for carcinogenicity testing. However. at the present time, it is not appropriate to make regulatory decisions based on transgenic animal bioassays because we do not have the sufficient knowledge base that is required in order to make informed decisions. Specifically, we lack adequate confidence in a negative response, (e.g., Will a negative 24-week test be superceded if it is repeated for 36 weeks and yields a positive response?) and we do not have the ability to place a positive response into proper perspective (e.g., Will a transgenic mouse carcinogen quickly be referred to as a rodent carcinogen then a probable human carcinogen?). This presentation will focus on a critical, constructive analysis of proposed alternatives (e.g., the TG.AC, Hras2 and p53 +/ - ) with an emphasis on understanding the molecular basis of the models and juxtaposing this with our current view of carcinogenesis. I am in favor of change and I believe that transgenic animals may, eventually, aid in improving carcinogenicity testing. However, more hypothesis-driven research leading to a better understanding of the proposed models is required in order to be in a position to make sound regulatory decisions. Furthermore , it should be emphasized that our goal is not to create situations where we simply label more chemicals as rodent carcinogens. In this context. it is important to reiterate the necessity of concentrating on the basic issues: dose selection (including rational criteria for selecting the high dose ), shape of the dose-response curve (including the existence of thresholds), and species to species extrapolat ion.
D2. Debate2
Debates
I02/1 [ BIOMARKERSARE OF LITTLE PRACTICALVALUE IN CANCEREPIDEMIOLOGY (AGAINSn
Dl. Debate 1
I01/1 [
TRANSGENIC ANIMAL MODELS ARE AN APPROPRIATE ALTERNATIVE TO THE SECONDSPECIESIN TESTING FOR CARCINOGENICITY OF PHARMACEUTICALS (FOR)
H. Van Cauteren. Janssen Research Foundation. B-2340 Beerse,
Belgium As specified in the ICH process . a survey of six pharmaceutical data bases revealed that the use of one species (rats or mice) in two-year testing would not result in loss of information on carcinogenicity relevant to human risk assessment for human pharmaceuticals. The conduct of only one two-year study will allow investment in other, shorter-term models such as those using transgenic mice. This conduct will mean not only an investment in future models. but, as such, the results obtained from these transgenic mouse models will
S.R. Tannenbaum. Massachusetts Institute of Technlogy,
Cambridge. MA. USA The types of biomarkers used in cancer epidemiology include biomarkers of: internal dose of carcinogens, biological effects of carcinogen exposure, precancerous lesions, and cancer. The utility of any biomarker is related to its prior validation in separate studies and its appropriate application in well-designed epidemiological investigations. This side of the debate will be confined to biomarkers of internal dose in relation to disease outcome. The rules of causality in epidemiological studies must be applied, particularly those of biological plausability and temporali ty. The rules of analytical chemistry also apply, particularly those of accuracy. precision, and chemical identity. It will be demonstrated through specific cases that when the rules are followed biomarkers may be of great value for the study of metabolic polymorphisms, identification of cryptic exposures, association of exposures with risk of cancer, and for prudent public health decisions.