James D. Wilson

A scheme for classifying carcinogens

We present a scheme for classifying chemical carcinogens according to the weight of the evidence that each substance poses a human cancer hazard. The approach represents a logical extension of and builds upon those previously developed by the International Agency for Research on Cancer, the U.S. Environmental Protection Agency, and the so-called Tripartite Group of industrial scientists. It takes into account new scientific knowledge about chemical carcinogenesis and animal models. Eight categories are presented: known human carcinogen (Category 1), carcinogenic activity in animals, probable human carcinogen (Category 2), possible human carcinogen (Category 3), equivocal evidence for carcinogenic activity (Category 4), evidence inadequate for classification (Category 5), carcinogenic activity in animals; probably not a human cancer hazard (Category 6), carcinogenic activity in animals; considered not a human cancer hazard (Category 7), evidence of noncarcinogenicity (Category 8). Evidence useful for categorization includes human studies, animal bioassays, corroborative evidence from bioassays, and mechanistic studies relevant to determining the predictivity of animal responses for human hazard. Weighing this evidence to derive a conclusion about classification is a process that requires expert judgment; it cannot now be reduced to a simple set of decision rules. However, we identify the kinds of information that can be useful in this process, and indicate how each might most appropriately be used.

Classification of electrically conducting ‘electron-transfer’ compounds by crystal structure

Organic and metal-organic electron-transfer solids can be classified by crystal structure, those known to date being divided intohomosoric, in which identical molecules stack infinitely,heterosoric, in which different molecules stack alternately, andnonsoric, non-stacked types. Only homosoric solids have high electrical conductivity.

Δ2,2′-Bis-(4,5-dicyano-1,3-dithiolidene)

Δ2,2′-Bis-(4,5-dicyano-1,3-dithiolidene) is prepared quantitatively by the reaction of trimethyl phosphite with 4,5-dicyano-1,3-dithiol-2-one.

BIOLOGICAL BASES FOR CANCER DOSE-RESPONSE EXTRAPOLATION PROCEDURES

The Moolgavkar-Knudson theory of carcinogenesis of 1981 incorporates the viable portions of earlier multistage theories and provides the basis for both the linearized multistage and biologically based dose-response extrapolation methodologies. This theory begins with the premise that cancer occurs because irreversible genetic changes (mutations) are required for transformation of normal cells to cancer cells; incidence data are consistent with only two critical changes being required, but a small contribution from three or higher mutation pathways cannot be ruled out. Events or agents that increase the rate of cell division also increase the probability that one of these critical mutations will occur by reducing the time available for repair of DNA lesions before mitosis. The DNA lesions can occur from background causes or from treatment with mutagenic agents. Thus, the equations describing incidence as a function of exposure to carcinogenic agents include two separate terms, one accounting for mutagenic and one for mitogenic stimuli. At high exposures these interact, producing synergism and high incidence rates, but at low exposures they are effectively independent. The multistage models that are now used include only terms corresponding to the mutagenic stimuli and thus fail to adequately describe incidence at high dose rates. Biologically based models attempt to include mitogenic effects, as well; they are usually limited by data availability.

Assessment of Low-Exposure Risk from Carcinogens: Implications of the Knudson-Moolgavkar Two-Critical Mutation Theory

The two-critical-mutation carcinogenesis theory of Knudson and Moolgavkar seems to provide solutions to some of the most contentious problems in cancer risk assessment. It describes a class of agents which increase tumor incidence without being reactive toward DNA: these nongenotoxic agents act through increases in cell birth rate. Because mutations occur when DNA lesions are not repaired before mitosis, increasing the mitotic rate increases the probability that a critical mutation will occur. Agents which affect mitotic rate can act either on normal cells or on those which have undergone one of the two critical mutations (“initiated”). Those acting on initiated cells are identified with the class called “promoters” by experimentalists. No unequivocal examples of agents acting solely on normal cells have yet been reported, although some are postulated.

Electrically Conducting Salts of 11, 11, 11 12, 12-Tetracyano-2,6-Naphthoquinodimethane (TNAP)

Abstract The electron-accepting molecule 11,11,12,12-tetracyano-2,6-naphthoquinodimethan(TNAP) forms electrically-conducting solid salts similar in conductivity to those formed by the related TCNQ. Salts of TNAP with both metallic (Na, K, Tl, Cu) and organic (e.g., methyltriphenylphosphonium, N-methylphenazinium) counter-ions were prepared and characterized, and their electrical conductivities measured. The activation energies of Ph3MeP(TNAP)2, and similar TCNQ salts are related to a structural parameter. The N-methylphenazinium salt was prepared in two allotropic forms. Improvements in the reported TNAP synthesis are described.

Assessment of Risks from Acute Hazards at Monsanto

Handling acutely hazardous materials safely is a skill that the modern chemical industry developed as it grew. The low rate of injury from exposure to reactive and dangerous substances such as chlorine, phosphorus, sulfuric acid, hydrogen cyanide, and ammonia testifies to that skill. Recently the changing structure of the industry, and especially the Bhopal disaster, have caused us to focus anew on risks from such materials. This paper describes Monsanto’s approach.

An Extremely Simple Preparation of Ethylenedinitrilobis(2-Pent-3-En-4-Olato) Nickel

Abstract The ligand of the title complex is prepared, simply and in high yield, by the condensation of ethylenediamine with acetylacetone in aqueous bicarbonate solution. Addition of a nickel salt to the completed reaction mixture causes the formation and crystallization of the title complex, again in high yield