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Appendix 1
Application of the IPCS Conceptual Framework for Cancer Risk Assessment
(IPCS Framework for Analysing the Relevance of a Cancer Mode of Action for Humans):
consideration of mammary gland tumours in female Sprague-Dawley rats exposed to atrazine
This framework, developed by an International Programme on Chemical safety (IPCS) working
group, provides a generic approach to the principles commonly used in evaluating a postulated
mode of action (MOA) for tumour induction by a chemical (Boobis et al., 2006). The framework was
used by the 2007 JMPR to provide a structured approach to the assessment of the overall weightof-evidence
for the postulated MOA for the increased incidence of mammary tumours (adenomas,
carcinomas, fibroadenomas) in rats that was observed after long-term administration of atrazine.
The first stage of the framework is to determine whether it is possible to establish an MOA.
This process comprises a series of key events along the causal pathway to cancer, identified using
a weight-of-evidence approach on the basis of the Bradford-Hill criteria. The key events are then
compared first qualitatively and then quantitatively between the experimental animals and humans.
Finally, a statement of confidence, analysis, and implications is provided.
Mammary gland tumours associated with atrazine exposure in female Sprague-Dawley rats
I. Is the weight of evidence sufficient to establish an MOA in animals?
1. Introduction
In seven studies of carcinogenicity in Sprague-Dawley rats fed diets containing atrazine at
concentrations of up to 1000 ppm (equal to about 42 and 65 mg/kg bw per day in males and females,
respectively), an increased incidence and/or an earlier appearance of spontaneously occurring mammary
tumours (adenomas, carcinomas, fibroadenomas) was observed in four studies, while in two
studies, there was an earlier appearance of mammary tumours, without any increase in their overall
lifetime incidence (see monograph section 2.3).
2. Postulated MOA (theory of the case)
The postulated MOA for mammary tumours induced by atrazine in female Sprague-Dawley rats
involves disruption of the hypothalamic–pituitary–ovary axis. Atrazine modifies catecholamine function
and the regulation of gonadotropin-releasing hormone (GnRH) pulsatility in the rat hypothalamus, with
the consequence that the pulse of luteinizing hormone (LH) released from the pituitary gland is of insufficient
amplitude or duration to trigger the ovulation. The failure to ovulate results in persistent secretion
of estrogen, which provides a feedback to the pituitary leading to increased secretion of prolactin. The
persistent stimulation of the mammary gland by estrogen and prolactin translates into a proliferative
response characterized by an earlier appearance and/or a higher incidence of adenocarcinomas (high
estrogen, moderate prolactin levels) or fibroadenomas (high prolactin with a background of estrogen)
(McConnell, 1989; O’Connor et al., 2000; Simpkins, 2000; Simpkins et al., 2000; Cooper et al., 2007).
3. Key events
The sequence of key events in the mode of carcinogenic action of atrazine in the mammary
gland of female Sprague-Dawley rats includes:
• Effect on the hypothalamus, leading to a modification of catecholamine function and the regulation
of GnRH pulsatility;
• In consequence, the pulse of LH released from the pituitary gland is of insufficient amplitude or
duration to trigger the ovulation;
ATRAZINE 37–138 JMPR 2007