Corticosteroidogenesis and StAR protein of rainbow trout disrupted by human-use pharmaceuticals: data for use in risk assessment.

Recent reports of presence of pharmaceutical drugs in surfacewaters (Kolpin et al., 2002; Metcalfe et al., 2004; Miao etal., 2002) raised concerns about the potential effects of thesechemicals in nontarget species, especially those in the aquaticenvironment (Trudeau et al., 2005). The study highlighted inthis issue, "Salicylate disrupts interrenal steroidogenesisand brain glucocorticoid receptor expression in rainbow trout"by Gravel and Vijayan (2006), demonstrated, using state-of-the-artmolecular tools in a well-characterized physiological modelrelevant for environmental toxicology, the disruption of corticosteroidogenesisby acetaminophen, ibuprofen, and salicylic acid, three human-usepharmaceuticals often detected in surface waters. Pharmaceuticals, substances designed to exert specific physiologicaleffects to prevent, cure, or alleviate symptoms of disease,include drugs,     

Focal adhesion kinase as a potential target in arsenic toxicity.

Arsenic is one of the highest priority hazardous substancesaround the world, and is well known for its toxicity and carcinogenicityin humans (National Research Council, 1999). Arsenic trioxidealso finds use as a remarkably effective chemotherapeutic agentin the treatment of acute promyelocytic leukaemia (APL), andmay find use in the treatment of certain solid tumors (Chenet al., 2002). This paradoxical nature of arsenic as a carcinogenicanti-cancer agent is dependent on the dose and duration of exposure,the status of various diseases, and the complex cellular interactionsof this remarkable metalloid (National Research Council, 1999;Qian et al., 2003). In this issue of Toxicological Sciences,Yancy et al. (pp. 1–9) reported the effects of sodium     

On the application of data on mode of action to carcinogenic risk assessment.

In the Forum article in this issue of Toxicological Sciences,Cohen et al. (2004) discuss a framework for systematic analysisof data on modes of carcinogenic action of chemicals in experimentalanimals, and its application to cancer risk assessment. Thissummarizes an exercise recently completed by the ILSI Risk ScienceInstitute (Cohen et al., 2003), which builds on a harmonizationinitiative of the International Programme on Chemical Safety(Sonich-Mullin et al., 2001). The framework approach is basedfundamentally on advances that have been achieved in recentdecades in understanding the pathogenesis of neoplasia. It isnow recognized that     

Dose thresholds should exist for chemical carcinogens.

To the Editor: Calculations showing that dose thresholds should exist for chemicalcarcinogens have been presented by this author in a series ofpublications (e.g., Waddell, 2002, 2003a–d). Subsequently,many investigators have challenged these calculations as flawed(e.g., Andersen et al., 2003; Crump and Clewell,     

Paraquat: the red herring of Parkinson's disease research.

Definitions adapted from the American Heritage Dictionary

Redherring n 1: something that draws attention away from thecentralissue

n 2: a smoked herring having a reddish color (they turnredwhen cured)

Folklore suggests that criminals attemptingto throw off pursuingbloodhounds would rub the fish acrosstheir trail

Definition from Monty Python and the Holy Grail

Herring n 3:an implement for felling mighty trees as suggestedby misguidedknights

After the discovery that 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine(MPTP) induced a parkinsonian syndrome in individuals who inadvertentlyinjected the by-product of illicit drug manufacturing (Langstonet al., 1983; Ramachandiran et al., 2007; Richardson et al.,2005     

Reply

To the Editor: The issue of carcinogenicity of bisphenol A was discussed inprevious letters to the editor (Huff, 2001; Munro et al., 2002).In his letter revisiting the subject, we note that Huff (2002)does not present any new information that was not previouslyaddressed. As we have already commented on the NTP findingsin our earlier letter (Munro et al., 2002), we have chosen topresent additional information in support of our findings withregard to the lack of carcinogenic potential of bisphenol A.However, we would first like to indicate that our original response     

Neurobehavioral effects of decabromodiphenyl ether (Deca) in neonatal mice.

To the Editor: May 13, 2004 Drs. Eriksson and Viberg responded to a Letter to the Editor(Vijverberg and van den Berg) regarding their report of neurobehavioraleffects of decabromodiphenyl ether (Deca) in neonatal mice (Toxicol.Sci. 76, 112–120; Viberg et al., 2003     

TO THE EDITOR

Phalen et al. (2006) have opened an important discussion ona key question of in vitro dosing of cells with poorly solubleparticles, focusing on tracheobronchial epithelial cells. Indeed,this paper is very timely, given the increasing number of publicationsusing exorbitantly high in vitro doses of particles and extrapolatingfrom those results potential adverse     

Highlight for phenols, quinolines, indoles, benzene and 2-cyclopenten-1-ones are oviduct toxicants in cigarette smoke, by Prue Talbot, Karen Riveles, and Ryan Rosa: list of tobacco-smoke constituents that are harmful for reproduction grows--passive smokers may be at risk.

Epidemiological studies provide compelling evidence that smokinghas serious negative consequences on fertility and pregnancyoutcome. Numerous epidemiological studies have linked smokingwith higher frequency of ectopic pregnancies and problems relatedto the oviduct function (Castles et al., 1999). Smoking decreasesthe success rate of in vitro fertilization and, more specifically,reduces the rates of oocyte production (reviewed by Shiverickand Salafia, 1999). Clearly, we do not understand the exactmechanisms by which smoking decreases fertility and negativelyaffects pregnancy outcome. One of the reasons is the complexcomposition of the cigarette smoke,     

Prenatal Exposure to Phthalates and Intrauterine Inflammation: A Unifying Hypothesis

We read with great interest the recent paper by Xu et al. (2005),showing that phthalates alter rat placental essential fattyacids (EFA) homeostasis via peroxisome proliferator-activated     

To the Editor

In their recent publication in Toxicological Sciences Mitchellet al. (2007) report on the lung and systemic responses to carbonnanotubes (CNT) in mice. After 14 days of inhalation exposureto a maximum of 5 mg CNT/m³, no significant lung toxicity wasreported but immunological changes were noted in the spleen.These results contrast with the marked inflammatory and fibroticlung responses reported by other investigators who used singlewall CNT intratracheal (i.t.) injection in mice (Lam et al.,2004) or rats (Warheit et al.     

Nonanimal Alternatives for Skin Sensitization: A Step Forward?

For both animal welfare reasons as well as to meet the demandsof existing and impending legislation in Europe, there is anincreasing emphasis on the replacement of animals in toxicologytesting for end points such as skin sensitization (Basketterand Maxwell, 2007). However, many of the end points (chronictoxicity, teratology) may prove intractable, so there is a heavyfocus on end points such as irritation and sensitization. Inthis issue of Toxicological Sciences, there is a fascinatingnew paper by Natsch and Emter (2008) on how genes involved inthe response to antioxidants are impacted by exposure to chemicalswhich are     

Inhibition of Human Plasma and Serum Butyrylcholinesterase (EC 3.1.1.8) by {alpha}-Chaconine and {alpha}-Solanine

The purpose of these experiments was to determine the reversibilityof -chaconine and -solanine inhibition of human plasma butyrylcholinesterase(BuChE). For the substrate -naphthylacetate, optimal assay conditionswere 0.50 M sodium phosphate buffer and a substrate concentrationof 3–5 ' 10^–4 M. Dibucaine (1 ' 10^–5 M) indicatedthe usual phenotype for all subjects; -chaconine and -solanineat 2.88 ' 10^–6 M inhibited BuChE about 70 and 50%, respectively.One-and 24-hr incubations at 1 ' 10^–1 M with -chaconine,-solanine, paraoxon, eserine, and ethanol yielded reversibleinhibition with dilution except for paraoxon. Twenty-four-hourdialyses of incubations showed no inhibition except for paraoxon.PAGE enzyme activity gels of 1-and 24-hr incubations also showedno inhibition except for paraoxon. -Chaconine and -solanineare reversible inhibitors of human butyrylcholinesterase. Atestimated tissue levels, -chaconine, -solanine, and solanidineinhibited BuChE 10–86%. In assays which combined -chaconine,-solanine, and solanidine, inhibition of BuChE was less thanadditive. No inhibition of albumin -naphthylacetate esterase(an arylesterase) was noted with any inhibitor. The importanceof these data to adverse toxicological effects of potato alkaloidsis discussed.     

Communication Regarding Metabonomic Identification of Two Distinct Phenotypes in Sprague-Dawley (Crl:CD(SD)) Rats

In a recent publication, we reported the identification andcharacterization of two distinct phenotypes in Sprague-Dawleyrats obtained from the Charles River Raleigh facility (Roboskyet al., 2005). The phenotypes were designated as HIP (high hippuricacid level in urine) and CA (high chlorogenic     

The Effects of in Vitro and Aerosol Exposures to Cadmium on Phagocytosis by Rat Pulmonary Macrophages

The Effects of in Vitro and Aerosol Exposures to Cadmium onPhagocytosis by Rat Pulmonary Macrophages. GREENSPAN, B. J.,and MORROW, P. E (1984). Fundam. Appl. Toxicol. 4, 48–57.Aerosol exposures of rats were performed to assess the in vivoeffects of cadmium on the phagocytosis of latex particles bypulmonary macrophages. An in vitro assay for particle uptakewas devised which allowed quantification of phagocytosis byadhering and nonadhering macrophages. In vitro exposure to CdCl₂caused dose-dependent decreases in viability (trypan blue exclusion),percentage cells with particles, total number of particles phagocytized,and the ability of the macrophages to adhere to a siliconizedglass surface. In vivo effects were studied following 30-minaerosol exposures to 1.5 mg/m³ Cd (MMAD = 0.35 µm, _g =1.45) or 5.0 mg/m³ Cd (MMAD = 0.45 µm, _g = 1.60) as CdCl₂.Phagocytic activity in the in vitro test system was increasedimmediately and at Day 1 in the low exposure group. However,following exposure to 5.0 mg/m³ Cd, phagocytic activity wasdepressed until 8 days postexposure. The results show that cadmiumis capable of modifying the phagocytic ability of macrophagesin vivo as well as in vitro. Determinations of the total numberof particles phagocytized were found to be more sensitive thanpercentage cells phagocytizing in detecting the effects of cadmiumexposure.     

The Enhancing Effect of Spawning on Elimination of a Persistent Polychlorinated Biphenyl from Female Yellow Perch

The Enhancing Effect of Spawning on Elimination of a PersistentPolychlorinated Biphenyl from Female Yellow Perch. VODICNIK,M. J., AND PETERSON, R. E. (1985). Fundam. Appl. Toxicol. 5,770–776. Distribution and elimination of 2,5,2',5'-tetrachloro[¹⁴C]biphenyl.(4-CB) were studied for 6 months after exposing sexually maturefemale yellow perch to the compound in water and transferringthem to flowing 4-CB-free water. Perch that were exposed inJanuary spawned in May, and the study was terminated in June.During the first 4 months after exposure, the t for whole-bodyelimination was 22 weeks, primarily by elimination of 4-CB fromthe viscera and carcass. During spawning, enhanced elimination(t < 0.7 weeks) was due to the voiding of eggs containing4-CB. After spawning, whole-body elimination returned to a slowerrate (t = 16.3 weeks). Prior to the enhancement in 4-CB eliminationrate during spawning, there was a redistribution of 4-CB residueswithin the body of the perch which was characterized by a transferof 4-CB residues from primarily the carcass and viscera to eggs.Two weeks after exposure, 30% of the initial 4-CB body burdenwas distributed to the eggs, whereas just prior to spawning,about 50% was present in this tissue. These findings demonstratethat egg maturation and spawning result in a significant reductionin the body burden of a persistent polychlorinated biphenylin a lean-fish species.     

Letter.

To the Editor: Kodavanti et al.(2003) induced cardiomyopathy in Wistar Kyotorats by inhalation exposure to environmental combustion particlessimilar to ambient particulate matter and rich in bioavailablezinc. Myocardial degeneration, inflammation, and     

TO THE EDITOR

Gaylor et al. (2004) described a method of estimating the "zero-equivalentdose" (ZED) and a lower confidence limit for it (LZED), basedupon a quadratic polynomial dose-response model. They also suggesteda way to use the Environmental Protection Agency (EPA) benchmarkdose software to estimate these values, which was to selectthe continuous-response polynomial model and to use the "Point"benchmark response (BMR) type, setting it equal to the     

Site-specific, dose-dependent transitional analysis of toxicologic mechanisms: the interplay of local metabolic and physicochemical saturation.

When animal exposures are used to assess human risk to inhaledchemicals, the animals generally receive higher dose rates overshorter periods of time. This difference in dose rate and durationof exposure, when applied to risk extrapolation, creates a keychallenge: the challenge of accounting for the impact of doseand dose rate on possible transitions in mechanisms of toxicity(Slikker et al., 2004a,b). One such transition and the relatedmicrodosimetry are the subject of this issue's highlighted articleIncreasing Exposure Levels Cause an Abrupt Change in the Absorption