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Dioxins

3. What are the effects of dioxins in laboratory animals?

  • 3.1 What are the non-cancer effects on animals?
  • 3.2 Do dioxins cause cancer in laboratory animals?

3.1 What are the non-cancer effects on animals?

The source document for this Digest states:

Non-carcinogenic effects

A plethora of effects have been reported to occur in multiple animal studies following exposure to PCDDs, PCDFs and PCBs. The most extensive dataset on dose-response effects is available for 2,3,7,8-TCDD; less information is available for the other dioxin-like compounds. Therefore the focus of the evaluation of the animal data is on the effects of 2,3,7,8-TCDD.

Due to the multitude of different effects at various dose levels the most sensitive toxic and biochemical endpoints are presented in Table 1. In this table information on the lowest daily doses or body burdens resulting in the observed effects are included. The effects observed are each characterized either as an adverse (toxic) effect or as a biochemical and functional effect. The biochemical effects observed at the lowest body burdens, or tissue concentrations are early expressions of cascades of events induced by dioxin-like compounds that may or may not result in adverse effects in the animal or its progeny.

Among the most sensitive endpoints (on a body burden basis) are: endometriosis, developmental neurobehavioral (cognitive) effects, developmental reproductive (sperm counts, female urogenital malformations) effects, and immunotoxic effects, both adult and developmental . The most sensitive biochemical effects are CYP1A1/2 induction, EGF-receptor down-regulation and oxidative stress (Table 1).

The lowest doses giving rise to statistically significant effects in the most sensitive endpoints following exposure, have resulted in body burdens (e.g. 3 to 73 ng of TCDD/kg) in the exposed animals that overlap, at the lower end, the range of body burdens expressed as TEQ that are found in the general population in industrialized countries exposed to background levels of PCDDs, PCDFs and PCBs.

Source & ©: WHO-IPCS  Assessment of the health risk of dioxins:
re-evaluation of the Tolerable Daily Intake (TDI)
page 7

Table 1. MOST SENSITIVE EFFECTS OF 2,3,7,8-TCDD IN ANIMALS

Effect Species Exposure
(LOEL or LOAEL)
Maternal body burden (increment to background)*
* Background body burden in rats and mice is about 4 ng/kg (TEQ)s
** Body burden at the end of dosing period
*** Note: single dose
Adverse effects      
       
Developmental effects      
- neurotoxicity (object learning) Rhesus monkey ~160 pg/kg/d 42 ng/kg**
       
Reproductive toxicity rat    
- decreased sperm count   64,000 pg/kg*** 28 ng/kg**
- vaginal threads   200,000 pg/kg*** 73 ng/kg**
       
Immunotoxicity rat 100,000 pg/kg*** 50 ng/kg**
       
Immunological (viral sensitivity) mouse 10,000 pg/kg*** 10 ng/kg**
       
Hormonal (endometriosis) Rhesus ~160 pg/kg/d 42 ng/kg**
  monkey    
       
       
Effects which may or may not lead to adverse effects
       
Biochemical effects      
       
-CYP1A1 mouse 150 pg/kg/d 3 ng/kg
  rat 100 pg/kg/d 3 ng/kg
       
-CYP1A2 mouse 450 pg/kg/d 10 ng/kg
       
-EGFR rat 100 pg/kg/d 3 ng/kg
       
-IL1beta mouse 300 pg/kg/d ~10 ng/kg
       
Functional effects      
       
-oxidative stress mouse 450 pg/kg/d 10 ng/kg
       
-lymphocyte subsets marmoset ~200 pg/kg/d 6-8 ng/kg
  monkey     
       

Source & ©: WHO-IPCS  Assessment of the health risk of dioxins:
re-evaluation of the Tolerable Daily Intake (TDI)
page 7

3.2 Do dioxins cause cancer in laboratory animals?

The source document for this Digest states:

Carcinogenic effects

2,3,7,8-TCDD has been shown to be carcinogenic in several chronic studies at multiple sites in multiple species in both sexes. Short-term studies observed a lack of direct DNA-damaging effects including covalent binding to DNA by TCDD, which underscores that TCDD is not acting as an initiator of carcinogenesis. However, secondary mechanisms may be important in the observed carcinogenicity of TCDD and related dioxin-like compounds.

The lowest observed adverse effect of TCDD in the Kociba study was the development of hepatic adenomas in rats at an intake of 10 ng/kg bw/day and the no observed effect level was 1 ng/kg/day. At the no observed effect level, body burdens were 60 ng TCDD/kg bw.

TCDD also causes thyroid tumours in male rats. This has been indicated to proceed through a mechanism which involves altered thyroid hormone metabolism, and consequent increases in feedback mechanisms (TSH) which results in a chronic proliferative stimulation of thyroid follicular cells.

Studies in the mouse skin support a lack of initiating activity and an ability to promote the growth of previously initiated lesions indicative of a promoting agent. Mouse skin tumour promotion indicates that the Ah receptor is involved in tumour promotion by TCDD. Extensive examination of liver tumour promotion in the female rat liver also supports a non-genotoxic mechanism for the induction of liver neoplasms by TCDD. The ability of TCDD to enhance proliferation and inhibit apoptotic processes in focal hepatic lesions further supports an indirect mechanism of carcinogenicity.

Several PCDDs, PCDFs, non-ortho and mono-ortho PCBs have also been shown to be tumour promoters.

Source & ©: WHO-IPCS  Assessment of the health risk of dioxins:
re-evaluation of the Tolerable Daily Intake (TDI)
page 7-8


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