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Papers by Dan Heck

Abstract Certain inorganic nickel compounds such as crystalline NiS and Ni (, 3) S (, 2) are pote... more Abstract Certain inorganic nickel compounds such as crystalline NiS and Ni (, 3) S (, 2) are potent inducers of carcinogenesis and in vitro cell transformation, while several closely-related compounds such as amorphous NiS are essentially devoid of genotoxic activity. ...

Biological trace element research, 1984

This review has focused on several parameters related to the delivery of carcinogenic metal compo... more This review has focused on several parameters related to the delivery of carcinogenic metal compounds to the cell nucleus as a basis for understanding the intermediates formed between metals and cellular components and the effect of these intermediates on DNA structure and function. Emphasis has been placed on metal interactions at the cellular membrane, including lipid peroxidation, metal interactions with glutathione and their relation to membrane injury, and metal effects on the membrane bound enzyme, Na(+)/K(+) ATPase. Metal binding to metallothionein is also considered, particularly as related to transport and utilization of metal ions and to genetic defects in these processes exemplified in Menkes disease. The ability of cadmium to induce the synthesis of metallothionein more strongly than zinc is also discussed in relation to other toxic and carcinogenic metals. The effects of metal ions on purified DNA and RNA polymerase systems are presented with some of the recent studies ...

Cancer research, 1982

Crystalline NiS, CuS, CoS2, and CdS particles were actively phagocytosed by cells and potently in... more Crystalline NiS, CuS, CoS2, and CdS particles were actively phagocytosed by cells and potently induced morphological transformation of Syrian hamster embryo cells in a concentration-dependent fashion. In contrast, the respective amorphous metal sulfide particles (amorphous NiS, CuS, CoS, and CdS) were not as actively phagocytosed by cultured cells and, in comparison to the crystalline form of these compounds, induced considerably less morphological transformation at both cytotoxic and noncytotoxic exposure levels. Chemical reduction of positively charged amorphous NiS with LiAlH4 resulted in active phagocytosis of these particles which was also associated with enhancement of cellular transformation. Crystalline but not amorphous NiS caused considerable strand breaks in the DNA of Chinese hamster ovary cells following 2 to 3 hr exposure at 10 micrograms/ml as determined by alkaline sucrose gradient techniques with subsequent determination of DNA molecular weight. Phagocytized inert p...

Cancer research, 1983

Substantial evidence has accumulated which documents the active endocytosis by cells of particula... more Substantial evidence has accumulated which documents the active endocytosis by cells of particulate nickel compounds having potent carcinogenic and transforming capacity; compounds less potent in these respects exhibit a reduced tendency to be phagocytized by cultured fibroblasts. The surface charges (zeta potentials) of a number of particulate nickel compounds were measured in an attempt to identify the determinants of their variable degrees of cellular uptake. The carcinogenic particulates, crystalline NiS, Ni3S2, and NiO, exhibit strongly negative zeta potentials in distilled water and enter cells readily, while noncarcinogenic amorphous NiS, which is phagocytized to a lesser degree, is slightly positive in surface charge under similar conditions. The greater dissolution rate of amorphous NiS in comparison to crystalline NiS may contribute to its reduced uptake by cells by causing substantial alteration of the particle surface and/or by the generation of particle dissolution prod...

Progress in clinical and biological research, 1990

Biological Trace Element Research, 1982

The effects of serum components and amino acids on the uptake and cytotoxicity of NiCl2 were exam... more The effects of serum components and amino acids on the uptake and cytotoxicity of NiCl2 were examined in cultured Chinese hamster ovary (CHO) cells. CHO cells maintained in a minimal salts/glucose medium accumulated lO-fold more 63Ni than did cells maintained in complete medium supplemented with 10% fetal bovine serum. Cell-surface binding of 63Ni appeared to account for the majority of this increased accumulation of cell-associated nickel observed in the simple maintenance medium since such increases were reduced 70% by trypsin treatment. The addition of the Ni2+-binding amino acids cysteine or histidine to the salts/glucose medium markedly decreased 63Ni accumulations, an effect not observed following addition of any of several amino acids that do not bind Ni 2+. Supplementation of the salts/glucose medium with fetal bovine serum decreased in a concentration dependent fashion both the 63Ni 2+ uptake and cell detachment caused by Ni 2 § while dialyzed (amino acidfree) serum was 3-5-fold less effective than undialyzed serum at reducing 63Ni2+ uptake and similarly exhibited only a slight protective effect against nickel-induced cytotoxicity. Supplementation of dialyzed serum with cysteine at levels approximating those in whole serum partially restored its inhibitory activity toward nickel uptake by cells and restored completely its inhibition of nickel's cytotoxicity, indicating the predominant role of specific amino acids over serum proteins in regulating the uptake and subsequent cytotoxicity of Ni 2 §. Addition of cysteine to the salts/glucose medium during a 2 h exposure of cells to either 100 p34 HgC12 or 1 mM NiCI2 masked the cytotoxic effects of these metal ions. These results demonstrate the importance of extracellular small molecular weight metal ion chelators in altering the biological effects of metal ions at the level of metal uptake. Index Entries: Nickel, cytotoxicity of; serum components, and Ni uptake; amino acids, and Ni uptake; cytotoxicity of nickel; regulation, of nickel ion uptake.

Toxicology Letters, 1982

Various culture medium components were examined for their effect upon the phagocytosis of carcino... more Various culture medium components were examined for their effect upon the phagocytosis of carcinogenic crystalline and non-carcinogenic amorphous NiS by cultured fibroblastic cells using both a visual and radioactive assay for phagocytosis. Crystalline NiS was phagocytosed by cells in a simple salts/glucose maintenance medium to an extent similar to that observed in complex culture medium fortified with 10% fetal bovine serum (FBS), suggesting that serum proteins and other components in complex culture medium exert little influence upon the uptake of these heavy metal particles. Phagocytosis of crystalline NiS was shown to be highly dependent upon Ca2+ since omission of Ca2+ from the salts/glucose medium substantially reduced phagocytosis, while readdition of Ca2+ stimulated uptake in a concentration-dependent manner. The uptake of the NiS particles was inhibited by trifluoperazine, a calmodulin antagonist, implicating intracellular Ca2+ in this phagocytosis process. Since the opposite surface charge of crystalline and amorphous NiS has been related to their different phagocytic uptake by cells whose primary function is not phagocytosis (facultative phagocytes), these results show that the culture medium components do not modify the surface charge of these particles in a way that significantly influences their uptake.

Mutation Research Letters, 1993

During spot tests using Salmonella TA98 derivatives (YG1021, YG1024) and TA100 derivatives (YG102... more During spot tests using Salmonella TA98 derivatives (YG1021, YG1024) and TA100 derivatives (YG1026, YG1029), a unique response of O-acetyltransferase (OAT)-enhanced strains YG1024 and YG1029 to arylamines was observed. On plates containing rat-liver $9, these strains yielded revertant colonies induced in two separate concentric rings around the site of application, while the parent (TA98, TA100) and nitroreductase-enhanced strains (YG1021, YG1026) did not exhibit this response. The inner ring of revertants was accompanied by cytotoxicity and microcolony formation, with the outer ring in a region without background lawn toxicity. Addition of tetracycline to the top agar eliminated formation of the inner ring of YG1024 revertants in spot tests and reduced the revertant count in preincubation assays at cytotoxic dose levels of 2-aminoanthracene, 2-aminofluorene, 2-amino-6-methyldipyrido[1,2-a :3',2'd]imidazole and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline. Tetracycline sensitivity indicates that mutant colonies developing at high concentration/toxicity arose, in effect, from TA98 regenerated by functional loss of the tetracycline-resistance plasmid (pYG219) from YG1024. Mutant colonies found at low concentration/toxicity arose from normal plasmid-bearing YG1024. These results indicate the need to consider coincidental toxicity-induced instability in YG1024 during quantitative mutagenicity assays of arylamines and uncharacterized complex mixtures. Watanabe et al. (1989, 1990) have developed several Salmonella typhimurium strains with elevated nitroreductase (NR) or arylhydroxylamine : acetyl-CoA O-acetyltransferase (OAT)

JAMA: The Journal of the American Medical Association, 1998

Inhalation Toxicology, 2002

Glycerin (CAS no. 56-81-5) and propylene glycol (CAS no. 57-55-6) are commonly used as humectant ... more Glycerin (CAS no. 56-81-5) and propylene glycol (CAS no. 57-55-6) are commonly used as humectant ingredients in manufactured cigarettes to control and maintain the moisture content of the cut tobacco filler. The potential of these added humectants to affect the toxicity of cigarette smoke was investigated in a subchronic nose-only smoke inhalation study in rats. Filtered test cigarettes were prepared from an American-style tobacco blend containing either glycerin added at 5.1% w/w tobacco, propylene glycol at 2.2% w/w tobacco, or combinations of these humectants totaling 2.3%, 3.9%, and 7.2% w/w tobacco. Other groups of animals were exposed similarly to the smoke of reference cigarettes without added humectants, or to filtered air (sham control). Smoke exposures were conducted for 1 h/day, 5 days/wk for 13 wk, at target smoke particulate concentrations of 350 mg/m(3). All smoke-exposed groups had equivalent increases in blood carboxyhemoglobin, serum nicotine, and serum cotinine relative to the air controls. Smoke-associated reductions in body weights and occasional increases in heart and lung weights were generally similar among the various exposure conditions at necropsy. Increases in serum alkaline phosphatase and decreases in serum glucose and cholesterol were observed among smoke-exposed females relative to air controls. However, no significant differences in these parameters were evident between the humectant-containing and reference cigarette smoke exposure groups. Assessments of respiration conducted after 3, 6, 9, and 12 wk of smoke exposure indicated an initial smoke-related but not humectant-related decrease in respiratory rate, tidal volume, and minute volume during the first 20 min of each smoke exposure. Respiratory-tract histopathology was consistent across sexes and smoke groups, comprising (1) diffuse and focal alveolar pigmented macrophages and chronic interstitial inflammation in the lung, (2) laryngeal epithelial hyperplasia, squamous metaplasia, and scab formation, and (3) epithelial hyperplasia in the anterior nose. Smoke-related histopathology resolved substantially during a 6-wk postexposure recovery period. Addition of the tested humectants to cigarettes, singly or in combination, had no meaningful effect on the site, occurrence, or severity of respiratory-tract changes or on the measured indices of pulmonary function. It was concluded that the addition of glycerin and propylene glycol to cigarettes does not significantly affect the biological activity of inhaled cigarette smoke in this rat model.

Inhalation Toxicology, 1998

Four comparative two-stage SENCAR mouse skin painting bioassays were conducted with cigarette smo... more Four comparative two-stage SENCAR mouse skin painting bioassays were conducted with cigarette smoke condensate (CSC) preparations to evaluate the effect of common American cigarette flavoring ingredients on tumor promotion. Each independent study employed a unique flavoring combination applied to tobacco at exaggerated levels, and in total resulted in an evaluation of 150 ingredients. Groups of 30-50 female SENCAR mice each were initiated topically with 50 mg of 7,12-dimethylbenz(a)anthracene (DMBA), and promoted thrice weekly for 26 weeks with either 10 or 20 mg of CSC from test cigarettes containing ingredient mixtures. For comparison, separate groups of mice received concurrent treatment with CSC from reference cigarettes prepared without added ingredients. Negative and positive controls were treated with acetone or 12-0-tetradecanoyl-phorbol-13-acetate (TPA) as a promoter, respectively. CSC-only groups served as promotion controls. Tumors developed in \ 80% of the TPA-treated mice by study week 11, with a B3% background tumor formation in the acetone treated controls at termination. Tumor incidence in CSC-only promotion control groups was B20%, with no apparent difference between reference and test CSC groups. Approximately 70% of the DMBA-initiated mice promoted with 20 mg CSC developed tumors. Tumors first appeared around week 9, with about five tumors/tumor bearing animal. Tumor incidence, latency and multiplicity were CSC dose related, with a lower tumor incidence (approximately 50%), longer latency (12 weeks), and reduced tumor burden (four tumors/tumor bearing animal) at the 10 mg CSC dose level. While tumor incidence, latency and multiplicity data occasionally differed between test and comparative reference CSC groups, all effects appeared to be within normal variation for the model system. Furthermore, none of the changes appeared to be substantial enough to conclude that the tumor promotion capacity of CSC obtained from cigarettes containing tobacco with ingredients was discernibly different from the CSC obtained from reference cigarettes containing tobacco processed without ingredients.

Food and Chemical Toxicology, 1997

Menthol is a common pharmaceutical, food and tobacco flavouring ingredient used for its minty cha... more Menthol is a common pharmaceutical, food and tobacco flavouring ingredient used for its minty characteristics and cooling effects. A 13-wk comparative nose-only smoke inhalation toxicity study was conducted using an American-style, cellulose acetate-filtered, non-menthol reference cigarette and a similarly blended test cigarette containing 5000 ppm synthetic l-menthol tobacco. Male and female Fischer 344 rats were exposed for 1 hr/day, 5 days/wk for 13 wk at target mainstream smoke particulate concentrations of 200, 600 or 1200 mg/m3, while control rats were exposed to filtered air. Internal dose biomarkers (blood carboxyhaemoglobin, serum nicotine and serum continine) indicated equivalent exposures were obtained for the two cigarettes. Effects typically noted in rats exposed to high levels of mainstream tobacco smoke were similar for both cigarette types and included reduced body weights (males slightly more affected than females), increased heart-to-body weight ratios and lung weights, and histopathological changes in the respiratory tract. Rats exposed to reference cigarette smoke displayed a dose-related increase in nasal discharge that was not observed in menthol smoke-exposed rats. All smoke-related effects diminished significantly during a 6-wk non-exposure recovery period. The results of this 13-wk smoke inhalation study indicated that the addition of 5000 ppm menthol to tobacco had no substantial effect on the character or extent of the biological responses normally associated with inhalation of mainstream cigarette smoke in rats.

Food and Chemical Toxicology, 1992

Citral is a commonly used fragrance and flavour ingredient that has demonstrated a potential for ... more Citral is a commonly used fragrance and flavour ingredient that has demonstrated a potential for teratogenicity in chick embryo screening studies. To investigate potential mammalian developmental toxicity, pregnant Sprague-Dawley rats were exposed to citral by inhalation for 6 hr/day on gestation days 6-15 at mean concentrations of 0, 10 or 34 ppm as vapour, or 68 ppm as an aerosol/vapour mixture. Dams were killed on gestation day 20 and the foetuses were removed and evaluated for gross, visceral and skeletal malformations. Exposure to 68 ppm was maternally toxic, with reduced body-weight gains, ocular opacity, breathing difficulty, nasal discharge and salivation noted in the dams. No maternal toxicity was seen at the lower vapour exposure levels. The number of corpora lutea, implantations, resorptions, foetal viability, litter size, and sex ratio were not adversely affected by citral at any exposure level tested, and no exposure-related malformations were observed. At a maternally toxic exposure level, a slight reduction in mean foetal body weight and a slight increase in the incidence of hypoplastic bones were noted. Results of this study indicate that citral does not produce developmental toxicity in the rat when administered by inhalation at concentrations up to a maternally toxic exposure level.

Environmental Health Perspectives, 1989

Chronobiology International, 1991

The purpose of this study was to assess the reproducibility of any seasonal effects in the outbre... more The purpose of this study was to assess the reproducibility of any seasonal effects in the outbred CD1 mouse of antibody production to sheep red blood cells (SRBCs) and host resistance to the bacterium Listeria monocytogenes. A marked seasonal effect on antibody production was seen when 5- to 6-week-old female CD1 mice were studied on a weekly basis for a period of 2 years. Maintained on a 12:12 h light:dark schedule, animals were held for 12 days prior to experiment to insure physical condition and acclimatization to the lighting regimen. Beginning at 4 h after lights on (HALO) for day 1 and 2 HALO thereafter, groups of mice were (a) not treated, (b) administered a vehicle (corn oil, 1% methylcellulose, or distilled water) by oral gavage for 5 days, or (c) not treated, but given an intraperitoneal injection of cyclophosphamide 24 h prior to assay. On the fifth day, mice were injected with SRBCs intravenously. Four days later, antibody formation against SRBCs was measured using spleen cells. Circannual and seasonal rhythms were displayed by each group of animals, with greatest antibody production, indicated by the number of plaque-forming cells (PFCs)/million viable cells, in the Spring (range of double amplitude = 36-108%). The timing of these rhythms was reproducible from one year to the next. In contrast, the magnitude of the response in year 1 was significantly different from year 2 for animals given vehicle or not treated. Cyclophosphamide-treated mice had consistently low numbers of plaque-forming cells. Host resistance was studied in separate mice treated with vehicles at the same time as the antibody assay. On the third day of dosing, mice were injected intravenously with Listeria monocytogenes (LM) and monitored for death for 10 days. When analyzed by Kruskal-Wallis life table analysis, there was no overall effect of vehicle on survival for 1987 but there was an effect for 1988 and when data from both years were combined. Distilled water-treated mice had lower survival rates than the other two vehicles. Mice treated with distilled water displayed a circannual rhythm for survival for 1988 and for both years combined, in contrast to the other two vehicles. When each vehicle was analyzed separately for seasonal effect, a significant effect of season occurred for corn oil- and distilled water-treated animals. The greatest survival rate and longest survival time generally occurred in the months between July and December.

Chronobiology International, 1993

In order to confirm the presence of an acrophase difference based upon genotype in the seasonal e... more In order to confirm the presence of an acrophase difference based upon genotype in the seasonal expression of an immune competence end point, splenic plaque-forming cell (PFC) response to sheep red blood cells (SRBC), female B6C3F1 and CD1 mice were concurrently studied for PFC response during two studies performed in each season for 1 year. Mice were multiply housed, fed ad libitum, and standardized to light (06:00-18:00); dark (18:00-06:00). For each strain and study, subgroups were either naive (n = 10), received a vehicle (n = 10) or Cytoxan (n = 5). Challenge with SRBC occurred in early afternoon 4 days before harvesting of spleens and PFC assay. All other procedures were performed early in the daily light span. Analysis of variance and single cosinor analysis revealed a significant seasonal time effect for PFC in naive mice of both strains. Antibody formation was greatest in spring for CD1 mice and in summer for the B6C3F1 mice. These acrophases were consistent with earlier results for both strains and show the phenomena to be reproducible and genetically based.

Chemosphere, 1981

... IN SURFACE PROPERTIES OF AMORPHOUS AND CRYSTALLINE METAL SULFIDES MAY EXPLAIN THEIR TOXICOLOG... more ... IN SURFACE PROPERTIES OF AMORPHOUS AND CRYSTALLINE METAL SULFIDES MAY EXPLAIN THEIR TOXICOLOGICAL POTENCY Maria P. Abbracchio, J. Dan Heck, Richard M. Caprioli and Max Costa Div. ... 16) M. Costa, J. Nye, and FW Sunderman, Jr., Fed. ...

Carcinogenesis, 1982

Crystalline nickel sulfide (alpha NiS) and cobalt sulfide (CoS2) particles can cause greater cell... more Crystalline nickel sulfide (alpha NiS) and cobalt sulfide (CoS2) particles can cause greater cell transformation and cellular toxicity than the respective amorphous metal sulfide particles. Cultured mammalian cells phagocytose the crystalline metal sulfide particles more readily than the amorphous ones. In the case of the nickel sulfides, the crystalline metal sulfide particles had negatively charged surfaces (Zeta potential: -27.012 mV) in contrast to the amorphous particles, which were positively charge (Zeta potential: +9.174 mV). X-ray photoelectron spectroscopy analysis of amorphous and crystalline NiS particles revealed that the outermost surface (1-4 nm) of the two particles had striking differences in Ni/S ratios and in their sulfur oxidation states. Rendering particles&amp;#39; surfaces more negative by reduction with lithium aluminum hydride enhanced their phagocytosis, and in the case of amorphous NiS chemical reduction resulted in an incidence of morphological transformation of Syrian hamster embryo cells comparable to that observed with untreated crystalline alpha NiS.

Cancer Letters, 1982

The incidence of morphological transformation following exposure of Syrian hamster embryo (SHE) c... more The incidence of morphological transformation following exposure of Syrian hamster embryo (SHE) cells to crystalline alphaNiS particles was considerably greater than that following a similar exposure to amorphous NiS particles. These differences in potency were attributable to the selective phagocytosis of crystalline alphaNiS particles into cells, since untreated amorphous NiS particles were not readily taken up. Chemical reduction of the amorphous NiS particles' surface with LiAlH4 resulted in an increase both in their phagocytic uptake by Chinese hamster ovary (CHO) cells and in their ability to induce transformation in SHE cells. The phagocytosis and transforming activity of crystalline alphaNiS particles was also enhanced by LiAlH4 reduction. These results are consistent with previous observations showing that untreated crystalline NiS particles have a negative surface charge while amorphous NiS particles possess positively charged surfaces. These findings support the general hypothesis that the transforming activity of particulate metal compounds is proportional to their phagocytic uptake. Specifically, these observations show that the entry of metal sulfide particles into cells is related to their surface properties and, in particular, to the degree of negative charge on the surface microenvironment.