The Glaring Gap in Chemical Safety Testing

William H. Goodson III, MD and Shanaz Dairkee, PhD

Not many of us would advise a patient to take aspirin, ibu-

profen, and clopidogrel at the same time. In combination, these chemicals – and all drugs are just chemicals with identified clinical uses – interact such that the effect of the combination is much greater than the effect of the chemicals individually. Adverse effects are anticipated if these three drugs are taken simultaneously.

Most of us wouldn’t personally consider taking three antiplatelet drugs simultaneously. However, every day, each of us is exposed to mixtures of chemicals, and there is no reason to expect that these mixed environmental chemicals won’t also interact in ways that exceed the effects of the individual chemicals. Yet, almost all research by the FDA, IARC, etc. has either studied chemicals individually - or dry labbed the effects of mixtures by assuming that the combined effects of the component chemicals can be calculated in silico, i.e., by computer, from the observed effects of individual chemicals.

In 2015, the Halifax Project proposed the Low-Dose Mixtures Hypothesis of Carcinogenesis. Behind this hypothesis was an international group of 168 specialists in Hallmarks of Cancer who reviewed published data on how a variety of supposedly safe chemicals affected different Hallmarks of Cancer, with the specification that reviewed chemicals were not considered carcinogens. The group found published research supporting concern that mixtures of low concentrations of supposedly safe chemicals might activate individual Hallmarks of Cancer (one or more Hallmark by each chemical) such that the mixture of supposedly safe chemicals might activate all Hallmarks and function, in combination, as a virtual carcinogen. At the California Pacific Medical Center Research Institute, we have measured the effects of chemical mixtures on non-malignant, human breast epithelial cells. For example, we measured effects of three common chemicals of commerce (methylparaben = MP; bisphenol-a = BPA; Perflurooctanoic acid = PFOA) on S-phase as a marker of cell growth rate (1). In the figure, the y-axis is S-phase expressed as the number of times control (1 is the same as control S-phase, 2 is twice control, 3 is thrice control, etc.). On the x-axis the Intermediate doses1 are levels measured in humans. Low (L) doses are one tenth of Intermediate. High (H) doses are 10 times Intermediate. As anticipated, the mixture caused higher S-phase.

More important, however, mixtures of chemicals behaved like they were present at ten-times higher concentrations. A mix of Low doses of the three chemicals cause increased S-phase equal to any of the individual three chemicals at the ten-times higher Intermediate dose (left arrow in figure). Similarly, a mix of chemicals at the Intermediate dose was equal to any of the three chemicals at a ten-times higher, High dose (right arrow).

The next frontier is whether new effects occur after exposure to mixtures. Do we just see more of the same? Or, do mixtures cause unique effects, not seen after exposure to any of the individual chemicals alone.

Available research indicates that unique effects occur after exposure to chemical mixtures. The founders of the Halifax Project, Drs. Leroy Lowe, David Carpenter, and Michael Gilbertson, and I reviewed the literature of empirical observations of actual mixtures2. There was a worrying paucity of research using chemical mixtures. However, eight papers reported that mixtures of chemicals caused effects not observed after exposure to the component chemicals alone. Such unique effects of mixtures are missed when researchers dry lab results.

Safety data concerning chemical mixtures is clearly insufficient, and providing scientific advice is nearly impossible. However, every time we avoid one chemical we reduce the complexity of the mixture to which our bodies must adjust. My personal choices for 2021 are to limit my intake of residues of agricultural chemicals and to avoid the chemicals used for scents in personal care products.

References

1 Dairkee, SH, et al. A ternary Mixture of Common Chemicals Perturbs Benign Human Breast Epithelial Cells more than the Same

Chemicals do Individually. Toxicol Sci. 2018; 165:131-144 PMID 29846718 2. Goodson, WH, et al. Testing the low dose mixtures hypothesis.

Rev Environ Health. 2020 August Online ahead of print. PMID: 32833669

William H. Goodson III, MD is past President of the San Francisco Medical Society, former Professor of Surgery at University of California San Francisco, a Senior Scientist at the California Pacific Medical Center Research Institute, and a practicing physician in San Francisco.

Shanaz Dairkee, PhD is a Senior Scientist at the California Pacific Medical Center Research Institute and a member of the California Proposition Assessment Committee.