EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY 



The National Toxicology Program describes the results of individual experiments on a chemical agent and notes the strength of 

 the evidence for conclusions regarding each study. Negative results, in which the study animals do not have a greater incidence 

 of neoplasia than control animals, do not necessarily mean that a chemical is not a carcinogen, inasmuch as the experiments are 

 conducted under a limited set of conditions. Positive results demonstrate that a chemical is carcinogenic for laboratory animals 

 under the conditions of the study and indicate that exposure to the chemical has the potential for hazard to humans. Other 

 organizations, such as the International Agency for Research on Cancer, assign a strength of evidence for conclusions based on 

 an examination of all available evidence including: animal studies such as those conducted by the NTP, epidemiologic studies, 

 and estimates of exposure. Thus, the actual determination of risk to humans from chemicals found to be carcinogenic in labora- 

 tory animals requires a wider analysis that extends beyond the purview of these studies. 



Five categories of evidence of carcinogenic activity are used in the Technical Report series to summarize the strength of the evi- 

 dence observed in each experiment: two categories for positive results ("Clear Evidence" and "Some Evidence"); one category 

 for uncertain findings ("Equivocal Evidence"); one category for no observable elTects ("No Evidence"); and one category for ex- 

 periments thatbecauseofmajor flaws cannot be evaluated ("Inadequate Study"). These categories of interpretative conclusions 

 were first adopted in June 1983 and then revised in March 1986 for use m the Technical Reports series to incorporate more 

 specifically the concept of actual weight of evidence of carcinogenic activity. For each separate experiment (male rats, female 

 rats, male mice, female mice), one of the following quintet is selected to describe the findings. These categories refer to the 

 strength of the experimental evidence and not to either potency or mechanism. 



• Clear Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing a dose-related 

 (i) increase of malignant neoplasms, (ii) increase of a combination of malignant and benign neoplasms, or (lii) marked 

 increase of benign neoplasms if there is an indication from this or other studies of the ability of .-lUch tumors to progress 

 to malignancy. 



• Some Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing a chemically 

 related increased incidence of neoplasms (malignant, benign, or combined) m w. hich the strength of the response is le.ss 

 than that required for clear evidence. 



• Equivocal Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing a mar- 

 ginal increase of neoplasms that may be chemically related. 



• No Evidence of Carcinogenic Activity is demonstrated by studies that are interpreted as showing no chemically re- 

 lated increases in malignant or benign neoplasms. 



• Inadequate Study of Carcinogenic Activity is demonstrated by studies that because of major qualitative or quanti- 

 tative limitations cannot be interpreted as valid for showing either the presence or absence of carcinogenic activity. 



When a conclusion statement for a particular experiment is selected, consideration must be given to key factors that would ex- 

 tend the actual boundary of an individual category of evidence. This should allow for incorporation of scientific experience and 

 current understanding of long-term carcinogenesis studies in laboratory animals, especially for those evaluations that may be 

 on the borderline between two adjacent levels. These considerations should include: 



• The adequacy of the experimental design and conduct; 



• Occurrence of common versus uncommon neoplasia; 



• Progression (or lack thereof) from benign to malignant neoplasia as well as from preneoplastic to neoplastic lesions; 



• Some benign neoplasms have the capacity to regress but others (of the same morphologic type) progress. At present, it 

 is impossible to identify the difference. Therefore, where progression is known to be a possibility, the most prudent 

 course is to assume that benign neoplasms of those types have the potential to become malignant; 



• Combining benign and malignant tumor incidences known or thought to represent stages of progression in the same or- 

 gan or tissue; 



• Latency in tumor induction; 



• Multiplicity in site-specific neoplasia; 



• Metastases; 



• Supporting information from proliferative lesions (hyperplasia) in the same site of neoplasia or in other experiments 

 (same lesion in another sex or species); 



• The presence or absence of dose relationships; 



• The statistical significance of the observed tumor increase; 



• The concurrent control tumor incidence as well as the historical control rate and variability for a specific neoplasm; 



• Survival-adjusted analyses and false positive or false negative concerns; 



• Structure-activity correlations; and 



• In some cases, genetic toxicology. 



Nitrofurantoin, NTP TR 341 



