LEAD Action News
LEAD Action News vol 11 Number 2, December 2010, ISSN 1324-6011
Incorporating Lead Aware Times (ISSN 1440-4966) & Lead Advisory Service News (ISSN 1440-0561)
The journal of The LEAD (Lead Education and Abatement Design) Group Inc.
Guest Editor, Dr Chrissie Pickin. Editor-in-Chief: Anne Roberts

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Synergism at Low Levels of Exposure?

By Rosalind Harrison, Toxicologist, Environmental Health Unit,
Department of Health and Human Services

Humans are constantly exposed to a wide variety of man-made and naturally occurring chemicals simultaneously (Feron et al 1998, Sexton and Hattis 2007). This poses challenges to risk assessors because many different types of chemical mixtures can occur in the environment, and the hazards associated with such combined exposures may be different from when chemicals are considered individually (De Rosa et al 2004). Furthermore, there is an increasing awareness in the general population of simultaneous exposure to chemicals. Rosebery is a heavily mineralised area, and hence the Rosebery mine has operated continuously since 1936, with current potential beyond 2020. From the extensive environmental sampling program carried out by GHD consultants, in consultation with the mine operators, Minerals and Metals Group and the Environment Protection Authority, it is known that a number of metals exist in combination in the Rosebery environment.

Humans have always been exposed to metals, either through natural geological occurrence, resulting in contamination of food crops and drinking water, or through pollution from industrial and other human activities (Carpenter et al 2002, Lu and Kacew 2009). Some metals are essential to health, but may be toxic at high levels of exposure. Other metals have no known beneficial function, and long-term, high-level exposures may be harmful to health (Lu and Kacew 2009).

There are different ways in which chemicals can interact (ATSDR 2001, WHO 2009). Synergism comes from the Greek word ‘synergos’, meaning working together, and is one type of toxicological interaction. Synergism occurs when the effect caused by exposure to two or more chemicals at the same time is greater than the sum of the effects of the individual chemicals (CCOHS 2004). More simply, synergism is when a mixture of chemicals produces a stronger effect than could otherwise be predicted, i.e. more than additive, such as 1 plus 1 is greater than 2. Synergy is a public health concern because exposure to individual chemicals, which are considered to be safe, might pose unacceptable health risks when exposure occurs simultaneously to a combination of such chemicals. Therefore, the potential hazards of any chemical mixture need to be considered. Other types of interaction from exposure to mixtures can also occur; e.g. “additive” (when 1 plus 1 equals 2), or “protective” (when the presence of one substance reduces uptake of, or inhibits harm from another – e.g. zinc can reduce absorption of cadmium) (ATSDR 2001).

Synergistic interactions are known to occur in some situations. For example, there is a higher incidence of lung cancer resulting from simultaneous exposure to asbestos and tobacco smoke (through smoking), than would be expected from simple addition of the effects of asbestos and tobacco smoke acting independently (Erren et al 1999). However, synergistic effects such as this have only been shown to occur at high levels which are probably unrepresentative of the exposure levels present naturally in the environment. At relevant environmental exposures, i.e. low (non-toxic) doses, interactions between chemicals have not been shown to occur. Synergistic effects are typically only observed at high exposures – well above the toxicity threshold for each individual chemical; and it has been proposed that there is an interaction ‘threshold’, below which interactions in chemical mixtures are unlikely to be relevant (Feron et al 1998, Konemann and Pieters 1996, Yang and Dennison 2007).

The Department of Health and Human Services (DHHS) undertook to address concerns regarding the presence of metals in soil and groundwater in Rosebery and the possibility that these metals may be interacting synergistically. The DHHS has considered whether there is any evidence that synergistic interactions can occur following exposure to a range of metals in the environment, including whether adverse human health effects can occur despite normal biomonitoring data. Focussing on interactions associated with exposure to lead, arsenic, manganese, together with their potential interactions with other metals, the DHHS has concluded from the available evidence that interactions between metals have not been shown to occur at low levels of exposure for each individual metal (ATSDR 2004a, ATSDR 2004b, Choudhury and Mudipalli 2008, Wang and Fowler 2008). The understanding of the DHHS, supported by toxicologists who were consulted for advice, is that synergistic interactions and any resultant adverse health effects are associated only with high levels of exposure - at or above the individual toxicity threshold level for the metals concerned.

Overall, there is no evidence that low levels of exposure to mixtures of arsenic, lead and manganese in the Rosebery environment (based on the biomonitoring results) is resulting in synergistic interactions.


  1. ATSDR (Agency for Toxic Substances and Disease Registry) (2001) Guidance for the preparation of an interaction profile United States Department of Health and Human Services, Atlanta USA.
  2. ATSDR (Agency for Toxic Substances and Disease Registry) (2004a) Interaction profile for: arsenic, cadmium, chromium, and lead United States Department of Health and Human Services, Atlanta USA.
  3. ATSDR (Agency for Toxic Substances and Disease Registry) (2004b) Interaction profile for: lead, manganese, zinc, and copper United States Department of Health and Human Services, Atlanta USA.
  4. Carpenter, DO; Arcaro, K; Spink, DC. (2002) Understanding the human health effects of chemical mixtures Environmental Health Perspectives 110(1) 25-41.
  5. CCOHS (Canadian Centre for Occupational Health and Safety) (2004) Synergism, accessed on 16/09/10. www.ccohs.ca/oshanswers/chemicals/synergism.html
  6. Choudhury, H; Mudipalli A. (2008) Potential considerations & concerns in the risk characterization for the interaction profiles of metals Indian Journal of Medical Research 128(4) 462-483.
  7. De Rosa, CT; El-Masri, HA; Pohl, H; Cibulas, W; Mumtaz, MM. (2004) Implications of chemical mixtures in public health practice Journal of Toxicology and Environmental Health (7) 339-350.
  8. Erren, TC; Jacobson, M; Piekarski, C. (1999) Synergy between asbestos and smoking on lung cancer risks Epidemiology (10) 405-411.
  9. Feron, VJ; Cassee, FR; Groeten, JP. (1998) Toxicology of chemical mixtures: international perspective Environmental Health Perspectives 106(6) 1281-1289.
  10. Konemann, WH and Pieters MN. (1996) Confusion of concepts in mixture toxicology Food and Chemical Toxicology 34(11-12) 1025-1031.
  11. Lu, FC; Kacew, S. (2009) Toxicity of metals Lu’s Basic Toxicology: Fundamentals, Target Organs, and Risk Assessment Informa Healthcare USA.
  12. Sexton, K; Hattis, D. (2007) Assessing cumulative health risks from exposure to environmental mixtures – three fundamental questions Environmental Health Perspectives 115(5) 825-832.
  13. Wang, G; Fowler, BA. (2008) Roles of biomarkers in evaluating interactions among mixtures of lead, cadmium and arsenic Toxicology and Applied Pharmacology 233(1) 92-99.
  14. WHO (World Health Organization) (2009) Assessment of combined exposures to multiple chemicals: Report of a WHO/IPCS international workshop IPCS Harmonization Project Document 7 World Health Organization 2009.
  15. Yang, RS; Dennison JE. (2007) Initial analyses of the relationship between “Thresholds” of toxicity for individual chemicals and “Interaction Thresholds” for chemical mixtures Toxicology and Applied Pharmacology 223(2) 133-138.

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