An approach for the delineation of a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances as a pragmatic tool to fulfill REACH requirements.

Under the current European legislation for the Registration, Evaluation, Authorisation and restriction of Chemicals (REACHs) a Derived No Effect Level (DNEL) has to be delineated for acute and chronic inhalation effects. The majority of available experimental studies are performed by the oral route of exposure. Route to route extrapolation poses particular problems for irritating or corrosive substances but the necessity for additional animal studies with inhalation exposure needs to be balanced with the regulatory information requirements. Existing occupational exposure limits (OEL) as surrogate for cut-off limits representing safe exposure under working conditions were grouped under certain criteria for substances that are legally classified in Europe as irritating or corrosive. As a result, it was shown that the OEL for irritating substances in this dataset is not lower than 10mg/m(3) and for corrosives not lower than 1mg/m(3). Under certain conditions these generic limits could be applied as a pragmatic, but still sufficiently reliable and protective upper cut-off limit approach to avoid additional animal tests with irritating or corrosive chemicals. The respective systemic toxicity profiles and physical-chemical properties need to be considered. Specific exclusion criteria for the discussed concept apply.

Evaluation of time extrapolation factors based on the database RepDose.

In chemical risk assessment for many substances only short-term animal studies are available for the evaluation of long-term human exposure. Therefore usually extrapolation factors (EF) are used to extrapolate NOAELs from existing short-term studies to NOAELs for long term exposure. In this report time EFs are derived, based on NOEL/C or LOEL/C ratios (short term N(L)OEL/long term N(L)OEL) from the large datasets of the database RepDose (www.fraunhofer-repdose.de) on repeated dose toxicity for oral or inhalation administration. Within a tiered approach several sources of variability, e.g. use of LOEL/C ratios or differences in dose spacing were analyzed and if needed subsequently excluded. The reduction of data variability resulted in "final" EFs datasets, which are as far as possible based on compound-specific, time-dependent differences in toxicity. For distribution functions of oral repeated dose toxicity studies characterised by GM, GSD and 90th percentiles the following data are obtained: subacute-to-subchronic - GM 1.3, GSD 2.4, 90th 4.0, subacute-to-chronic - GM 3.4, GSD 3.7, 90th 18.2, and subchronic-to-chronic - GM 1.4, GSD 2.1, 90th 3.6. The number of data for inhalation exposure is limited, but with regard to systemic toxicity the derived EFs confirm the respective oral EFs.

Investigations on the effects of alkyl polyglucosides on development and fertility.

Alkyl polyglucosides are non-ionic surfactants which are mainly used in laundry detergents, hard surface cleaners and personal care products. Two in vitro screening test systems were used to investigate the endocrine modulating potential of alkyl polyglucosides. No indications were observed for any estrogenic or anti-estrogenic effects in an MCF-7 E-Screen assay and a reporter gene assay using luciferase-transfected MCF-7 cells. Concentrations exceeding the effect concentration of estradiol by a factor of 1000 did not reveal any indication for an estrogenic activity. Furthermore, in a combination assay investigating the effects of estradiol in the presence of alkyl polyglucoside, no anti-estrogenic potential was observed. In an one-generation screening assay in rats no effects on the fertility were observed up to the highest dose of 1000 mg/kg bw/day alkyl glucoside. Potential embryo-/fetotoxicity and/or teratogenicity was investigated in a segment II study in rats. No effects were noted up to the limit dose of 1000 mg/kg bw/day. All parameters of the treatment groups were comparable with those of the control group. Skeletal and visceral investigations did not detect any treatment-related malformations. For the embryo/fetotoxicity, the teratogenicity and the maternal toxicity a NOAEL of 1000 mg/kg was deduced.

Chronic effect of antidopaminergic drugs or estrogen on male wistar rat lactotrophs and somatotrophs.

The aim of the present study was to evaluate the effect of antidopaminergic agents on the somatotrophs in the presence of hyperprolactinemia. Adult male Wistar rats were divided into 6 groups: a control group and five groups chronically treated (60 days) with haloperidol, fluphenazine, sulpiride, metoclopramide or estrogen. Somatotrophs and lactotrophs were identified by immunohistochemistry and the data are reported as percent of total anterior pituitary cells counted. The drugs significantly increased the percentage of lactotrophs: control (mean +/- SD) 21.3 +/- 4.4, haloperidol 27.8 +/- 2.2, fluphenazine 34.5 +/- 3.6, sulpiride 32.7 +/- 3.5, metoclopramide 33.4 +/- 5.5 and estrogen 42.4 +/- 2.8. A significant reduction in somatotrophs was observed in animals treated with haloperidol (23.1 +/- 3.0), fluphenazine (22.1 +/- 1.1) and metoclopramide (24.2 +/- 3.0) compared to control (27.3 +/- 3.8), whereas no difference was observed in the groups treated with sulpiride (25.0 +/- 2.2) and estrogen (27.1 +/- 2.8). In the groups in which a reduction occurred, this may have simply been due to dilution, secondary to lactotroph hyperplasia. In view of the duplication of the percentage of prolactin-secreting cells, when estrogen was applied, the absence of a reduction in the percent of somatotrophs suggests a replication effect on this cell population. These data provide additional information about the direct or indirect effect of drugs which, in addition to interfering with the dopaminergic system, may act on other pituitary cells as well as on the lactotrophs.

Chronic effect of antidopaminergic drugs or estrogen on male Wistar rat lactotrophs and somatotrophs

The aim of the present study was to evaluate the effect of antidopaminergic agents on the somatotrophs in the presence of hyperprolactinemia. Adult male Wistar rats were divided into 6 groups: a control group and five groups chronically treated (60 days) with haloperidol, fluphenazine, sulpiride, metoclopramide or estrogen. Somatotrophs and lactotrophs were identified by immunohistochemistry and the data are reported as percent of total anterior pituitary cells counted. The drugs significantly increased the percentage of lactotrophs: control (mean + or - SD) 21.3 + or - 4.4, haloperidol 27.8 + or - 2.2, fluphenazine 34.5 + or - 3.6, sulpiride 32.7 + or - 3.5, metoclopramide 33.4 + or - 5.5 and estrogen 42.4 + or - 2.8. A significant reduction in somatotrophs was observed in animals treated with haloperidol (23.1 + or - 3.0), fluphenazine (22.1 + or - 1.1) and metoclopramide (24.2 + or - 3.0) compared to control (27.3 + or - 3.8), whereas no difference was observed in the groups treated with sulpiride (25.0 + or - 2.2) and estrogen (27.1 + or - 2.8). In the groups in which a reduction occurred, this may have simply been due to dilution, secondary to lactotroph hyperplasia. In view of the duplication of the percentage of prolactin-secreting cells, when estrogen was applied, the absence of a reduction in the percent of somatotrophs suggests a replication effect on this cell population. These data provide additional information about the direct or indirect effect of drugs which, in addition to interfering with the dopaminergic system, may act on other pituitary cells as well as on the lactotrophs.

Factoring handedness data: II. Geschwind's multidimensional hypothesis.

The challenge in this journal by Peters and Murphy to the validity of two published factor analyses of handedness data because of bimodality was dealt with in Part I by identifying measures to normalize the handedness item distributions. A new survey using Oldfield's questionnaire format had 38 bell-shaped (unimodal) handedness-item distributions and 11 that were only marginally bimodal out of the 55 items used in Geschwind's 1986 study. Yet they were still non-normal and the factor analysis was unsatisfactory; bimodality is not the only problem. By choosing a transformation for each item that was optimal as assessed by D'Agostino's K2 statistic, all but two items could be normalized. Seven factors were derived that showed high congruence between maximum likelihood and principal components extractions before and after varimax rotation. Geschwind's assertion that handedness is not unidimensional is therefore supported.

Factoring handedness data: I. Item analysis.

Recently in this journal Peters and Murphy challenged the validity of factor analyses done on bimodal handedness data, suggesting instead that right- and left-handers be studied separately. But bimodality may be avoidable if attention is paid to Oldfield's questionnaire format and instructions for the subjects. Two characteristics appear crucial: a two-column LEFT-RIGHT format for the body of the instrument and what we call Oldfield's Admonition: not to indicate strong preference for handedness item, such as write, unless "... the preference is so strong that you would never try to use the other hand unless absolutely forced to...". Attaining unimodality of an item distribution would seem to overcome the objections of Peters and Murphy. In a 1984 survey in Boston we used Oldfield's ten-item questionnaire exactly as published. This produced unimodal item distributions. With reflection of the five-point item scale and a logarithmic transformation, we achieved a degree of normalization for the items. Two surveys elsewhere based on Oldfield's 20-item list but with changes in the questionnaire format and the instructions, yielded markedly different item distributions with peaks at each extreme and sometimes in the middle as well.

Handedness and headache.

A California handedness study involved 199 male and 74 female cluster headache sufferers as well as 477 migraineurs. Earlier reported data indicated that cluster headache patients had a left-handedness prevalence of over 15%. With the current data the prevalence in males was 11.0% and in females, 8.2%. The corresponding migraine figures were 11.8% and 8.1%. The cluster and migraine headache groups did not differ significantly from each other or from the expected 10% frequency of left-handedness in either sex.

Overlap of migraine and tension-type headache in the International Headache Society classification.

Using questionnaire data from two recent surveys, headache sufferers were classified as having either migraine, episodic, or chronic tension-type headache using the International Headache Society criteria. Of 410 subjects with a headache history of 2 years or more, 147 or 35.9% were assigned Code 1.7 (migrainous disorder not fulfilling the above criteria) or Code 2.3 (headache of the tension-type not fulfilling above criteria). In 79 of these 147 subjects (53.7%), either of the above codes would have been equally valid. Separate scores for "migraine" and "tension" symptoms may provide a way to handle this overlap and aid in choosing optimal therapy.

A questionnaire survey of muscular symptoms in chronic headache. An age- and sex-controlled study.

In a questionnaire survey we determined the prevalence and intensity of muscular symptoms in a group of chronic headache sufferers as compared with age- and sex-matched controls. The muscular symptoms studied were tightness and soreness of the neck, shoulder, and jaw muscles. Muscle tightness was reported significantly more frequently in the headache than in the control group, but only for the neck muscles (48.6 vs. 29.9%; p less than 0.01). When headache was present, the prevalence of neck muscle tightness in the headache group significantly increased further to 68.8% (p less than 0.001) and that of jaw muscle tightness increased significantly from 17.2 to 29.7% (p less than 0.01). The intensity of muscle tightness was again only significantly different between the headache and the control groups for the neck muscles (p less than 0.01). However, it was significantly higher for all three muscle groups in the headache group when headache was actually present than when headache was absent (p less than 0.001). With regard to the prevalence of muscle soreness, there were no significant differences between the headache and the control groups or within the headache group when headache was absent or present. However, the intensity of muscle soreness was significantly greater for all three muscle groups in the headache group when headache was present than when headache was absent (p less than 0.001). The results indicate significant muscular symptoms in relation to headache, particularly in relation to the neck muscles, with tightness standing out more than soreness.

Reading problems in adult chronic headache sufferers.

In a questionnaire survey we determined the prevalence of problems with reading, at present as well as in the past, in adult chronic headache sufferers as compared with age- and sex-matched controls. The reading problems inquired about were those with reading in general, reading quickly, prolonged reading and reading comprehension. The subjects were also asked about present and past problems with writing, concentrating, performing mathematics and overall learning. Significant differences in the prevalences of the problems studied between the headache sufferers and controls were observed on just two items and only for the female groups. These items were present problems with reading comprehension (39.3% versus 7.5%; p = 0.002) and concentrating (46.4% versus 17.5%; p = 0.015). We concluded that adult female headache sufferers have impaired reading comprehension and concentration abilities which do not seem to originate from the past.

Headache and family history.

In two headache questionnaire surveys we inquired about the occurrence of headache in the mothers, fathers, siblings and children of the respondents. In total, 633 people completed valid questionnaires, 260 in the first survey and 373 in the second. The hypothesis was that familial headache occurrence would be positively associated with headache frequency. In each survey, the regression of headache frequency on the number of parents having headache was highly significant. Neither sex nor the sibling and children variables were significant predictors. In the cross-tabulations of the parental occurrence of headache with headache frequency we saw a clear "break-point" between the "no headache" and the headache frequency categories studied. For the final analyses the dichotomy "headache/no headache" was related in fourfold tables to headache occurrence in the father and the mother separately, and to the number of headache parents. The positive associations were not simply due to the large number of migraine cases since they remained after removing the migraineurs.

A controlled study of visual symptoms and eye strain factors in chronic headache.

In a questionnaire survey we determined the prevalence of visual symptoms and eye strain factors in a group of chronic headache sufferers as compared with age- and sex-matched controls. The visual symptoms studied were those not specific for headache, i.e., sensitivity to light and blurred vision. Sensitivity to light in the absence of headache was reported by 27.8% of controls and 44.7% of headache sufferers (p less than 0.05). The latter figure increased to 71.3% when headache was actually present (p less than 0.001). Blurred vision occurred in 13.5% of controls and 7.4% of headache sufferers (not significant). In the presence of headache, the latter figure increased to 44.7% (p less than 0.01). Of the eye strain factors studied, bright light was reported to precipitate headache in 29.3% and to aggravate it in 73.4%. For reading, these figures were 16.0% and 55.3%, respectively; for working at the computer screen, 14.5% and 31.3%; and for watching television, 6.4% and 27.7%. We conclude that visual symptoms are more common in chronic headache and eye strain factors more important than is generally recognized.

Migraine and left-handedness: is there a connection?

In 1982, Geschwind and Behan reported an association between migraine headache and left-handedness. The present study was an attempt to test this hypothesis by comparing the frequency of left-handedness in migraine and tension headache patients at a headache center. Cluster headache cases were also included because Geschwind and Behan suspected that the association might be even stronger in this disorder. A special scoring method for handedness was devised by Geschwind and Behan to help identify a possible higher risk in mixed-handedness subjects. No significant associations emerged in any of these tests. A modest association of cluster headache and left-handedness disappeared when adjustment was made for the strong predilection of cluster headache for the male sex.

Flunarizine vs. pizotifen in migraine prophylaxis: a review of comparative studies.

Six double-blind studies have been published in which the efficacy of flunarizine and pizotifen were compared. In none of the studies were differences of statistical significance revealed for attack frequency. Secondary analysis of the three studies in which the same protocol was employed, using parametric tests on transformed data gave similar results. Pooling of the data in an attempt to enhance the power by enlarging the number of patients, actually decreased the power due to an increase in standard deviation.