Screening for human urinary bladder carcinogens: two-year bioassay is unnecessary

Area of Science:

• Toxicology
• Carcinogenesis
• Urothelial Biology

Background:

• Traditional two-year rodent bioassays for carcinogen screening have limitations in human relevance regarding mode of action (MOA) and dose-response.
• Existing methods often lack direct applicability to human risk assessment for urinary bladder cancer.

Purpose of the Study:

• To introduce a novel, multi-step, 90-day screening process for urinary bladder carcinogens.
• To develop a more efficient, cost-effective, and human-relevant alternative to the conventional two-year rodent bioassay.

Main Methods:

• Initial screening for urothelial proliferation (microscopy or Ki-67 labeling index).
• Subsequent analysis of mode of action (MOA), DNA reactivity, and cytotoxicity, including evaluation of urinary solids and *in vitro* cell line assays.
• Dose-response assessment for chemicals exhibiting cytotoxicity without urinary solid formation.

Main Results:

• The proposed 90-day screening process reliably identifies known human urinary bladder carcinogens and those found in rodent bioassays.
• The method integrates MOA and dose-response analyses, enhancing its relevance for human risk assessment.
• The short-term assay provides a more efficient and less expensive alternative to long-term bioassays.

Conclusions:

• The proposed 90-day screening strategy offers a reliable, cost-effective, and human-relevant approach to assess urinary bladder carcinogenicity.
• This method provides crucial MOA and dose-response data for improved human cancer risk assessment.
• The short-term screening process is a significant advancement over traditional two-year rodent bioassays.