Figure 1.Dose-response curve.
Previously, susceptible populations and resistant populations were identified primarily so that they could be excluded from analysis (i.e., to avoid misestimating the effects on the “normal” population) (Hattis 1996). However, as detailed in the following chapter, environmental health scientists interested in human genetic variation in response to environmental chemicals define susceptibility (and, less often, resistance) as a primary focus of their research.
In a second definition of gene-environment interaction, environmental health scientists contend that in order to understand—and intervene in—the effects of environmental exposures on human health, one must identify their effects on genes and gene expression. For example, a molecular epidemiologist explained that her research on gene-environment interaction focused on:
. . . actually proving that people had these compounds, these carcinogenic compounds, inside them . . . [and] had damaged DNA because of these carcinogens. See, before that, all we had was the industrial hygiene people [who] would tell us, “yes, these people have inhaled carcinogens or PAHs, or benzene or something.” And maybe there were some assays, some urine-type assays, showing that people were excreting them. But the molecular [biomarkers], the adduct assays were the first to show that these compounds actually interacted with, and permanently bound to things like DNA (Interview S12, emphasis added).
This definition encompasses research on environmental mutagenesis, DNA repair mechanisms (and their impairment), and epigenetics; it is also a defining focus of molecular epidemiology.
This second definition of gene-environment interaction—with its focus on how environmental chemicals affect genes and their functioning—was already built into the infrastructure of the NIEHS and NTP. From its inception, genetic damage was “identified as a component of environmental hazards” of interest at the NIEHS (Barrett, Oral History Interview February 2004). During the 1970s, NIEHS scientists (many of whom had transferred from the Biology Division of the Oak Ridge National Laboratory) established the field of genetic toxicology (Frickel 2004), which focused originally on “the potential of chemicals to induce heritable changes in germ cells that lead to genetic disorders in subsequent generations” (Shelby, Oral History Interview April 2004).10 Many of these researchers shared an interest in developing short-term tests to “study the mechanisms of chemically induced DNA damage and to assess the potential genetic hazard of chemicals to humans” (Tennant et al. 1987). In the early 1970s, the work of Bruce Ames and his colleagues made a strong connection between DNA damage and cancer and provided a relatively easy mutagenesis bioassay—the Salmonella test—to identify carcinogens (Ames et al. 1973).11 Soon thereafter, following the advocacy of prominent environmental health scientists, short-term tests for mutagenesis were “enshrined in regulatory requirements and in biomedical research more generally as carcinogenicity screens” (Frickel 2004). As such, there was significant genetic toxicological infrastructure and expertise at the NIEHS and NTP.
Research on the molecular mechanisms of carcinogenesis has been another site for the development of research on gene-environment interaction at NIEHS. As Carl Barrett, formerly the Scientific Director of NIEHS, recalled, “There was not much of an emphasis in the early days, the first decade of the NIEHS, on cancer because there was a cancer institute. So there was . . . an intentional focus away from cancer to distinguish NIEHS from NCI [National Cancer Institute].” However, beginning in the late 1970s, “there was a growing interest and involvement in cancer [research] within the institute” (Barrett, Oral History Interview February 2004). In 1987, the NIEHS founded the Laboratory of Molecular Carcinogenesis (LMC) and charged it to “elucidate the genes involved in the [cancer] process and use that information to understand how the environment impacts it” (Barrett, Oral History Interview February 2004). By focusing on the role of environmental chemicals in cancer causation, the LMC added complexity to then ascendant scientific explanations of genes as the primary basis of cancer causation (Fujimura 1996): “While we were doing the molecular analysis, we were also studying how a number of environmental chemicals worked . . . [and] we developed a paradigm for thinking about how environmental health worked—that health and disease [are] a consequence of the interaction between ones genes and environment over time” (Barrett, Oral History Interview February 2004).
In addition to the flexibility of this paradigm across varied scientific disciplines (with their different definitions of gene-environment interaction and ways of studying it) and stakeholders in the environmental health arena (with their different investments in the process of risk assessment and regulation), it has been importantly flexible over time.
[All the major genomics initiatives at NIEHS] were part of a greater strategy of trying to bring new technologies and new concepts to bear in terms of environmental health sciences, and they really are extensions of the concept of gene-environment over time (Barrett, Oral History Interview February 2004).
The ability of the concept of gene-environment interaction to be extended over time has meant, in practice, that new technologies and research agendas can be subsumed under its aegis. For example, in 1997, the major genomics initiative at NIEHS centered on sequencing genes that conferred susceptibility to environmental exposures (i.e., environmental genomics); by 2001, NIEHS had also launched a major effort to use microarrays to study the effects of environmental chemicals on gene expression (i.e., toxicogenomics). More recently, researchers have promoted the promise of epigenetics by referring to gene-environment interaction (Olden et al. 2011). Research on gene-environment interaction has been undertaken with a staggering array of techniques, including high-throughput gene sequencers, molecular biomarkers, cDNA and protein microarrays, genome-wide association studies, and quantitative PCR, to name just a few. Thus, the concept of gene-environment interaction has engaged environmental health scientists even as the substantive foci, technologies, and concepts at the center of research shift and change.
CRITIQUING THE CONSENSUS CRITIQUE
Despite its rhetorical strengths and successes, not all environmental health scientists have been persuaded by the consensus critique. NIEHS administrators freely admitted that scientists whom they referred to as “traditional toxicologists” were “not happy” with changes underway at the NIEHS and NTP and referred me to their colleagues for “dissenting” opinions (Field Notes, NIEHS 2002).
However, given the scope of the proposed and ongoing changes to their field, it was surprisingly difficult to find scientists who were critical of research on gene-environment interaction or, related, the development of molecular genetic and genomic techniques for risk assessment. In the one overt exception, a scientist referred to toxicogenomics as “crapola” and contested the relevance of research on molecular mechanisms to the NTP’s public health mission:
. . . everybody coming out of school in the last 15 years are all molecular, DNA is the answer, which [it] may be and which is fine. But [at NTP] we need some people with practicality. We need some people with [skills in] toxicology . . . empirical descriptive toxicology. [If] you find out something causes cancer, then let somebody else mess around with the mechanism. . . . I don’t want to know how it does it . . . I want to know, “Is this safe?” (Interview S97).
Further, a few scientists took issue with the promise of individual techniques of studying gene-environment interaction, noting, for example their “skepticism” regarding research being done in specific transgenic mouse models (even while endorsing research being done with other transgenic mouse models) (Interview S96). However, on the whole, those scientists identified by their peers as dissenters commented on the successes of their field, built on traditional approaches to assessing risks and preventing exposures, rather than offering a critique of emerging molecular approaches to environmental health research. For example, a toxicologist—who in the course of our interview told a colleague who dropped by that I was there to talk with her as “one of those who isn’t in the ‘genes will save us’ camp”—commented: “My interest is in, what can we change to make people healthier? We can change exposures. . . . You can’t