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Azam F. Tayabali and Verner L. Seligy

Mutagenesis Section, Environmental and Occupational Toxicology Division, Bureau of Chemical Hazards, Environmental Health Directorate, Health Protection Branch, Department of Health Canada, Ottawa, Ontario, Canada

Abstract

Most contemporary bioinsecticides are derived from scaled-up cultures of Bacillus thuringiensis subspecies israelensis (Bti) and kurstaki (Btk) , whose particulate fractions contain mostly B. thuringiensis spores (> 10¹²/L) and proteinaceous aggregates, including crystal-like parasporal inclusion bodies (PIB) . Based on concerns over relatedness to B. cereus-group pathogens, we conducted extensive testing of B. thuringiensis (BT) products and their subfractions using seven human cell types. The Bti/Btk products generated nonspecific cytotoxicities involving loss in bioreduction, cell rounding, blebbing and detachment, degradation of immunodetectable proteins, and cytolysis. Their threshold dose (Dt 5 10^-14% BT product/target cell) equated to a single spore and a target cell half-life (tLD₅₀) of approximately 16 hr. At Dts > 10⁴, the tLD₅₀ rapidly shifted to < 4 hr ; with antibiotic present, no component, including PIB-related -endotoxins, was cytolytic up to an equivalent of approximately 10⁹ Dt. The cytolytic agent(s) within the Bti/Btk-vegetative cell exoprotein (VCP) pool is an early spore outgrowth product identical to that of B. cereus and acting possibly by arresting protein synthesis. No cytolytic effects were seen with VCP from B. subtilis and Escherichia coli. These data, including recent epidemiologic work indicate that spore-containing BT products have an inherent capacity to lyse human cells in free and interactive forms and may also act as immune sensitizers. To critically impact at the whole body level, the exposure outcome would have to be an uncontrolled infection arising from intake of Btk/Bti spores. For humans, such a condition would be rare, arising possibly in equally rare exposure scenarios involving large doses of spores and individuals with weak or impaired microbe-clearance capacities and/or immune response systems. Key words: biopesticides, bioreduction, cell death, cytolytic factors, endotoxin, immunodetection, immune sensitization, ³⁵S-methionine, vegetative cells. Environ Health Perspect 108:919-930 (2000) . [Online 18 August 2000]

http://ehpnet1.niehs.nih.gov/docs/2000/108p919-930tayabali/ abstract.html

Address correspondence to V.L Seligy, Mutagenesis Section, Environmental and Occupational Toxicology Division, Environmental Health Centre, PL 0308A, Health Canada, Ottawa, Ontario, Canada K1A 0L2. Telephone: (613) 952-5852. Fax: (613) 941-4768. E-mail: vern_seligy@hc-sc.gc.ca

We thank D. Blakey, G. Douglas, D. Desaulniers, P. Shwed, and G. Coleman for reviewing the manuscript and providing helpful advice. Assistance in scanning electron microscopy analysis was provided by C. Chuang, Carleton University Centre for Electron Microscopy.

This work was supported by Health Canada (EHD intramural research program) , Industry Canada (National Biotechnology and Canadian Biotechnology Strategy Funds) , and Natural Sciences and Engineering Research Council (to V.L.S) .

Received 7 January 2000 ; accepted 2 May 2000.