Towards a mechanism-based approach for the prediction of nongenotoxic carcinogenic potential of agrochemicals

Figures & data

Figure 1. Distribution of the 411 substances over the different categories. Clockwise: Genotoxic carcinogen: positive in in vitro and in vivo genotoxicity/mutagenicity assays; Nongenotoxic carcinogen: substances with the reported treatment-related increase in incidence of benign or malignant tumors without in vivo evidence of genotoxicity; noncarcinogen: substance without reported treatment-related increase in incidence of benign or malignant tumors; Excluded: substance without sufficiently detailed or reliable tumor data available.

Figure 2. Number of treatment-related tumor types per each of the 170 nongenotoxic substances.

Figure 3. Organ distribution of all 340 observed treatment-related tumors with a suspected nongenotoxic MOA. The category “Other” includes bone, skin, eye, and prostate tumors.

Table 1. Summary table describing all discerned MOAs and MOA networks.

MOA/MOA network^a	Description	Organs	# Tumor cases	# Substances
Unknown		Various including: brain, lymphoid system, vascular, digestive tract.	116	74
Nuclear receptor (CAR and/or PXR) activation leading to induction of enzymes involved in xenobiotic metabolism	Sustained enzyme induction leading to hepatocellular adenoma/carcinoma	Liver	58	55
	Hepatic thyroid-hormone catabolism leading to sustained thyroid hormone production leading to follicular cell adenoma/carcinoma	Thyroid	42	40
	Hepatic steroid hormone catabolism leading to sustained hormone production leading to Leydig cell adenoma/carcinoma	Testes	5	5
	Hepatic hormone catabolism leading to sustained activation of HPT/HPG axis leading to pituitary adenoma/carcinoma	Brain	7	7
Sustained cytotoxicity	Sustained cytotoxicity leading to regenerative proliferation leading to tumor formation	Various including: (fore)stomach, kidney, bladder and intestine	61	45
Sustained cytotoxicity–oxidative stress	Oxidative stress leading to sustained cytotoxicity and increased cell proliferation leading to tumor formation	Various including: liver, spleen and lymphoid system	7	4
Endocrine-related MOAs	Sustained disruption of hormonal signaling leading to imbalance in hormone production leading to overstimulation of hormone sensitive tissue leading to tumor formation.	Various including: mammary gland, uterus, ovaries and testes	29	11
PPARα activation	PPARα activation leading to increased cell proliferation leading to hepatocellular adenoma /carcinoma	Liver	11	11
Thyroid Peroxidase inhibition	Thyroid peroxidase inhibition leading to sustained TSH production leading to sustained thyroid hormone production leading to follicular cell adenoma/carcinoma	Thyroid	4	4

^a For more details and references please see the respective MOA description.

Figure 4. The number of MOAs activated per each nongenotoxic carcinogen.

Figure 6. Overview of the number of tumors with an unidentified MOA. In total, there are 116 tumors in various organs induced by 74 unique substances.