Declaring the existence of human germ‐cell mutagens

Abstract

After more than 80 years of searching for human germ‐cell mutagens, I think that sufficient evidence already exists for a number of agents to be so considered, and definitive confirmation seems imminent due to the application of recently developed genomic techniques. In preparation for this, an assessment panel of internationally recognized experts in germ‐cell biology and genomics is required to consider either the current evidence now, or impending genomic evidence later, to declare whether an agent is a human germ‐cell mutagen. I propose that such a panel be organized under the aegis of the World Health Organization and constructed similarly to the working groups assembled by the International Agency for Research on Cancer for the evaluation of human carcinogens. Support from prominent national and international organizations would be important. Many regulatory agencies already have procedures in place for assessing potential human germ‐cell mutagens, and the time is approaching when definitive genomic data in humans will obligate such evaluations. In my view, application of an IARC‐type of assessment using available evidence leads to the conclusion that ionizing radiation, cancer chemotherapy, cigarette smoking, and air pollution are “Group 1” human germ‐cell mutagens. Consideration of the potential adverse health effects to the unexposed offspring of an exposed parent will usher in an entirely new realm of environmental health assessment. I suggest that the long search for human germ‐cell mutagens is about to end, and a demonstration of the much‐anticipated linkage between heritable disease and environmental factors is poised to begin. Environ. Mol. Mutagen. 2012. © 2012 Wiley Periodicals, Inc.

Investigating the effects of dietary folic acid on sperm count, DNA damage and mutation in Balb/c mice

“…As a result, much less is known about the environmental variables that influence germ cell mutation rates compared to somatic cells. To date, fewer than 50 mutagens have been studied for their ability to cause heritable mutations [3]. Existing evidence supports the germline mutagenicity of various agents including radiation, mutagenic anti-cancer drugs, and specific environmental mixtures (tobacco smoke, urban air pollution) [4][5][6][7][8][9][10][11].…”

A case-control study of paternal occupational exposures and the risk of childhood sporadic bilateral retinoblastoma

“…In addition, the generally modest agreement in exposure estimates between raters suggests that exposure measurement error may have affected results, with an unpredictable direction of bias for categorical exposures 30. The finding for radiation exposure seems particularly affected by random error and measurement error, given the definitive animal data and emerging human data on ionising radiation as a germline mutagen,31 including data on medical radiation from the same case-control study 5…”

Approaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays☆

“…Although germ cell mutation is an established regulatory endpoint, the appropriate assays exist, and more than 50 agents have been identified as germ cell mutagens in rodents, no agent has yet to be regulated solely as a germ cell mutagen, or evaluated to be a human germ cell mutagen. As data accumulate showing that cigarette smoke, air pollution, and ionizing radiation are likely human germ cell mutagens, this situation is expected to change soon [2].…”

“…The premise that the majority of carcinogens were somatic cell mutagens and could be readily detected with short-term assays resulted in a nearly complete shift in focus from heritable genetic hazards to somatic cell effects. Though, to date, no human germ cell mutagen has definitively been identified, nearly 50 rodent germ cell mutagens are known [2], and the consequences of heritable mutations remain of concern. BOX 1:…”