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Licensed Unlicensed Requires Authentication Published by De Gruyter August 24, 2020

Testing the low dose mixtures hypothesis from the Halifax project

  • William H. Goodson EMAIL logo , Leroy Lowe , Michael Gilbertson and David O. Carpenter


In 2013, 60 scientists, representing a larger group of 174 scientists from 26 nations, met in Halifax, Nova Scotia to consider whether – using published research – it was logical to anticipate that a mixture of chemicals, each thought to be non-carcinogenic, might act together in that mixture as a virtual carcinogen. The group identified 89 such chemicals, each one affecting one or more Hallmark(s) – collectively covering all Hallmarks of Cancer – confirming the possibility that a chemical mixture could induce all the Hallmarks and function as a virtual carcinogen, thereby supporting the concern that chemical safety research that does not evaluate mixtures, is incomplete. Based on these observations, the Halifax Project developed the Low-Dose Carcinogenesis Hypothesis which posits “…that low-dose exposures to [mixtures of] disruptive chemicals that are not individually carcinogenic may be capable of instigating and/or enabling carcinogenesis.” Although testing all possible combinations of over 80,000 chemicals of commerce would be impractical, prudence requires designing a methodology to test whether low-dose chemical mixtures might be carcinogenic. As an initial step toward testing this hypothesis, we conducted a mini review of published empirical observations of biological exposures to chemical mixtures to assess what empirical data exists on which to base future research. We reviewed studies on chemical mixtures with the criteria that the studies reported both different concentrations of chemicals and mixtures composed of different chemicals. We found a paucity of research on this important question. The majority of studies reported hormone related processes and used chemical concentrations selected to facilitate studying how mixtures behave in experiments that were often removed from clinical relevance, i.e., chemicals were not studied at human-relevant concentrations. New research programs must be envisioned to enable study of how mixtures of small doses of chemicals affect human health, starting, when at all possible, from non-malignant specimens when studies are done in vitro. This research should use human relevant concentrations of chemicals, expand research beyond the historic focus on endocrine endpoints and endocrine related cancers, and specifically seek effects that arise uniquely from exposure to chemical mixtures at human-relevant concentrations.

Corresponding author: William H. Goodson, Department of Surgery, California Pacific Medical Center Research Institute, 2100 Webster Street, Suite 401, San Francisco, CA94115, USA, Phone: +1 415 923 3925, Fax: +1 415 776 1977, E-mail:

Award Identifier / Grant number: 17UB-8702

Funding source: National Institute of Health-National Institute of Environmental Health Sciences

Award Identifier / Grant number: Conference travel grant R13ES023276

  1. Research funding: Goodson: The California Breast Cancer Research Program (17UB-8702). National Institute of Health-National Institute of Environmental Health Sciences. Conference travel grant R13ES023276.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.


Table 5:

Abbreviations for Tables 3 and 4.

2,3,4,5 TCBTetrachlorobiphenylol
2,4,6 TCBTrichlorbiphenylol
AGDAnogenital distance
AhRAryl hydrocarbon receptor
AHRRAhR receptor repressor
ARNTAhR nuclear translocator
ARSSodium arsenate
BDE 100Brominated diphenyl ether 100
BP3Benzophenone 3
BRCABreast cancer
CFUColony forming units
C×43Connexin 43
DCHPDicyclohexyl phthalate
EE2Ethinyl estradiol
EPEthyl paraben
EREstrogen receptor
EREEstrogen response element
ESR1Gene for ER-alpha
GDGestation day
HMECHuman mammary epithelial cells (benign)
HRBECHigh risk breast epithelial cell
HSDHydroxysteroid dehydrogenase
IHCImmunohistochemistry staining
LOAELLowest observed adverse effect level
MBCMethylbenzylidene camphor
MTTThiazolyl blue tetrazolium bromide
NHLNon-Hodgkins lymphoma
OCPOrganochloride pesticide
OHPCBHydroxylated polychlorinated biphenyl
PAHPolycyclic aromatic hydrocarbon
PCNAProliferating cell nuclear antigen
PFNAPerfluorononanoic acid
PFOAPerfluorooctanoic acid
PFOSPerfluorooctane sulfonate
PNDPost-natal day
PPARG(nuclear) peroxisome proliferator activated receptor gamma
PSPhenyl salicylate
PxRPregnane X receptor
resorcResorcinol monobenzoate
TBPCTrophoblast progenitor cell
TEXBTotal effective xenoestrogen burden
vCTBVillus cytotrophoblasts
YESYeast estrogen screen


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Received: 2020-03-13
Accepted: 2020-06-02
Published Online: 2020-08-24
Published in Print: 2020-11-18

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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