Chronic toxicity/oncogenicity study of styrene in CD-1 mice by inhalation exposure for 104 weeks.

Groups of 70 male and 70 female Charles River CD-1 mice were exposed whole body to styrene vapor at 0, 20, 40, 80 or 160 ppm 6 h per day 5 days per week for 98 weeks (females) or 104 weeks (males). The mice were observed daily; body weights, food and water consumption were measured periodically, a battery of hematological and clinical pathology examinations were conducted at weeks 13, 26, 52, 78 and 98 (females)/104 (males). Ten mice of each gender per group were pre-selected for necropsy after 52 and 78 weeks of exposure and the survivors of the remaining 50 of each gender per group were necropsied after 98 or 104 weeks. An extensive set of organs from the control and high-exposure mice were examined histopathologically, whereas target organs, gross lesions and all masses were examined in all other groups. Styrene had no effect on survival in males. Two high-dose females died (acute liver toxicity) during the first 2 weeks; the remaining exposed females had a slightly higher survival than control mice. Levels of styrene and styrene oxide (SO) in the blood at the end of a 6 h exposure during week 74 were proportional to exposure concentration, except that at 20 ppm the SO level was below the limit of detection. There were no changes of toxicological significance in hematology, clinical chemistry, urinalysis or organ weights. Mice exposed to 80 or 160 ppm gained slightly less weight than the controls. Styrene-related non-neoplastic histopathological changes were found only in the nasal passages and lungs. In the nasal passages of males and females at all exposure concentrations, the changes included respiratory metaplasia of the olfactory epithelium with changes in the underlying Bowman's gland; the severity increased with styrene concentration and duration of exposure. Loss of olfactory nerve fibers was seen in mice exposed to 40, 80 or 160 ppm. In the lungs, there was decreased eosinophilia of Clara cells in the terminal bronchioles and bronchiolar epithelial hyperplasia extending into alveolar ducts. Increased tumor incidence occurred only in the lung. The incidence of bronchioloalveolar adenomas was significantly increased in males exposed to 40, 80 or 160 ppm and in females exposed to 20, 40 and 160 ppm. The increase was seen only after 24 months. In females exposed to 160 ppm, the incidence of bronchiolo-alveolar carcinomas after 24 months was significantly greater than in the controls. No difference in lung tumors between control and styrene-exposed mice was seen in the intensity or degree of immunostaining, the location of tumors relative to bronchioles or histological type (papillary, solid or mixed). It appears that styrene induces an increase in the number of lung tumors seen spontaneously in CD-1 mice.

Chronic toxicity/oncogenicity study of styrene in CD rats by inhalation exposure for 104 weeks.

Groups of 70 male and 70 female Charles River CD (Sprague-Dawley-derived) rats were exposed whole body to styrene vapor at 0, 50, 200, 500, or 1000 ppm 6 h/day 5 days/week for 104 weeks. The rats were observed daily, body weights and food and water consumption were measured periodically, and a battery of hematologic and clinical pathology examinations was conducted at weeks 13, 26, 52, 78, and 104. Nine or 10 rats per sex per group were necropsied after 52 weeks of exposure and the remaining survivors were necropsied after 104 weeks. Control and high-exposure rats received a complete histopathologic examination, while target organs, gross lesions, and all masses were examined in the lower exposure groups. Styrene had no effect on survival in males, but females exposed to 500 or 1000 ppm had a dose-related increase in survival. Levels of styrene in the blood at the end of a 6-h exposure during week 95 were proportional to exposure concentration. Levels of styrene oxide in the blood of rats exposed to 200 ppm or greater styrene were proportional to styrene exposure concentration. There were no changes of toxicologic significance in hematology, clinical chemistry, urinalysis, or organ weights. Males exposed to 500 or 1000 ppm gained less weight than the controls during the first year and maintained the difference during the second year. Females exposed to 200, 500, or 1000 ppm gained less weight during the first year; those exposed to 500 or 1000 ppm continued to gain less during months 13-18. Styrene-related non-neoplastic histopathologic changes were confined to the olfactory epithelium of the nasal mucosa. There was no evidence that styrene exposure caused treatment-related increases of any tumor type in males or females or in the number of tumor-bearing rats in the exposed groups compared to controls. In females, there were treatment-related decreases in pituitary adenomas and mammary adenocarcinomas. Based on an overall evaluation of eight oncogenicity studies, there is clear evidence that styrene does not induce cancer in rats.

Twenty-eight-day repeated-dose inhalation exposure of rats to diethylene glycol monoethyl ether.

This study was carried out to provide information on the effects of inhalation of diethylene glycol monoethyl ether, a substance used in industry which may be accidentally inhaled by man. Sprague-Dawley CD rats were exposed by inhalation to a test atmosphere containing diethylene glycol monoethyl ether in a nose-only exposure system for 6 hr a day, 5 days a week for 28 days. Mean exposure levels were 0. 09, 0.27, and 1.1 mg/liter. At the two lowest exposure levels the test substance was present entirely as vapor, but at the highest exposure level the test atmosphere was approximately equally divided by mass into respirable droplets (aerosol) and vapor. A comprehensive battery of toxicological evaluations including food consumption, body weight, clinical signs, hematology, and biochemistry revealed no evidence of a systemic effect of exposure. Histopathological examination showed changes indicative of mild nonspecific irritation in the upper respiratory tract of rats exposed at the two highest exposure levels. These changes consisted of foci of necrosis in the ventral cartilage of the larynx of rats exposed at 0.27 or 1.1 mg/liter and an increase in eosinophilic inclusions in the olfactory epithelium of the nasal mucosa of rats exposed at 1.1 mg/liter. The no observed adverse effect level for systemic effects was 1.1 mg/liter and the no observed adverse effect level for signs indicative of mild nonspecific irritation of the upper respiratory tract was 0.09 mg/liter.

Subchronic inhalation studies of styrene in CD rats and CD-1 mice.

Groups of 10 male and 10 female Charles River (CRL) CD (Sprague-Dawley-derived) rats were exposed to styrene vapor at 0, 200, 500, 1000, or 1500 ppm 6 hr per day 5 days per week for 13 weeks. Styrene had no effect on survival, hematology, or clinical chemistry. Males at 1500 ppm weighed 10% less after 13 weeks and males and females at 1000 and 1500 ppm consumed more water than controls. Histopathologic changes were confined to the olfactory epithelium of the nasal mucosa. Groups of 20 male and 20 female CRL CD-1 and B6C3F1 mice were exposed to styrene vapor at 0, 15, 60, 250, or 500 ppm 6 hr per day 5 days per week for 2 weeks. Mortality was observed in both CD-1 and B6C3F1 mice exposed to 250 or 500 ppm; more female mice, but not males, died from exposure to 250 ppm than from 500 ppm. Groups of 10 male and 10 female CRL CD-1 mice were exposed to styrene vapors at 0, 50, 100, 150, or 200 ppm 6 hr per day 5 days per week for 13 weeks. Two females exposed to 200 ppm died during the first week. Liver toxicity was evident in the decedents and in some female survivors at 200 ppm. Changes were observed in the lungs of mice exposed to 100, 150, or 200 ppm and in the nasal passages of all treatment groups, those exposed to 50 ppm being less affected. Satellite groups of 15 male rats and 30 male mice were exposed as described above for 2, 5, or 13 weeks for measurement of cell proliferation (BrdU labeling). No increase in cell proliferation was found in liver of rats or mice or in cells of the bronchiolar or alveolar region of the lung of rats. No increase in labeling index of type II pneumocytes was seen in mouse lungs, while at 150 and 200 ppm, an increased labeling index of Clara cells was seen after 2 weeks and in occasional mice after 5 weeks. Large variations in the labeling index among animals emphasize the need for large group sizes. For nasal tract effects, a NOAEL was not found in CD-1 mice, but in CD rats, the NOAEL was 200 ppm. For other effects, the NOAEL was 500 ppm in rats and 50 ppm in mice.

Inhalation teratology and reproduction studies with 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123).

HCFC 123 is one of the chemicals being developed as a replacement for CFC 11 in refrigerant and solvent applications. Supplementing earlier rat teratology studies, a rabbit inhalation teratology study was conducted. In addition, one-generation and two-generation inhalation reproduction studies were conducted. In the teratology study, the pregnant rabbits were exposed to levels of 0 (control), 500, 1500, and 5000 ppm, 6 hr per day from Days 6 through 18 of gestation. Slight body weight losses and reduced food consumption were seen in does in all three exposure level groups. This response followed an exposure-related pattern. There were no other signs of maternal toxicity. There was also no evidence of treatment-related effects on the kits. A probe one-generation reproduction study was conducted. In this study four groups of 12 male and 12 female rats were exposed to vapors of HCFC 123 6 hr per day, 7 days per week from 4 weeks prior to mating through weaning of their offspring. The exposure levels for this study were 0 (control), 300, 1000, and 5000 ppm. There were no effects on mating and fertility, or on pup survival or birth weight. A two-generation study was subsequently conducted. In this study, five groups of 32 male and female rats were exposed to HCFC 123 from 6 weeks of age through weaning. From the offspring of these animals, groups of 28 males and females were selected for the F1 generation. These animals were exposed to HCFC 123 from weaning (4 weeks of age) through weaning of the F1 generation. All exposures were 6 hr per day, 7 days per week. The exposure levels for this study were 0 (control), 30, 100, 300, and 1000 ppm. There were no effects on any of the fertility or reproductive indices measured. As with prior studies, decreases in serum triglyceride levels were seen. Pup survival and birth weight were unaffected by treatment. Pup body weight gain was lower in all treatment groups during nursing, following an exposure-related pattern. Since weight gain for the F1 animals was normal following weaning, this depression of body weight gain may be related to the depression of serum triglycerides. In addition, liver weights of the adult rats exposed to levels of 100 ppm and higher of HCFC 123 were higher than controls, histological examination revealed only hepatic enlargement and vacuolation. It was concluded that exposure to HCFC 123 did not cause reproductive effects although it did effect the body weight gain of the offspring during lactation.

Effectiveness of an Indonesian model for rapid training of Guatemalan health workers in diarrhea case management.

The aim of this study was to assess the effectiveness of a newly developed method for rapid tiered training of health workers in improving community health worker knowledge and case management skills. The interactive "Kader" method, developed in West Java, Indonesia, was compared with traditional didactic training in a prospective trial with rural health workers ("Tecnicos") and village health promoters ("Promotores") for the Public Health Department in the state of Alta Verapaz, Guatemala. Twenty-five tecnicos received one day of training concerning diarrhea and dehydration. One group was trained using the interactive Kader method of Indonesia; the other with didactic methods. A sample of these tecnicos then trained 49 randomized promotores utilizing the same training method with which they were trained. The tecnicos and promotores in each group completed a case-based pre-test and post-test before and after their training sessions. Both tecnicos and promotores trained using the Kader tiered training approach demonstrated significantly greater improvement in their ability to correctly diagnose and recommend treatment for diarrhea of varying type and severity. Non-significant differences favoring the experimental groups were found in the tecnicos' and promotores' general knowledge regarding diarrhea prevention practices, signs of dehydration and preparation of oral rehydration solution. This pilot study suggests that the Kader method for rapid tiered training of health workers has applicability to the populations of other developing nations and can be recommended for large scale implementation and evaluation in the training of public health workers, village health promoters and families in Guatemala.

PIP: A study was conducted to assess the effectiveness of a newly developed method of rapid tiered training of health workers to improve their knowledge and case management skills. The interactive Kader method, developed in Indonesia, was compared with traditional didactic training in a prospective trial involving rural health workers and village health promoters in Alta Verapaz state. 25 rural health workers received one day of training on diarrhea and dehydration, one group with the Kader method and the other with didactic methods. A sample of the workers then trained 49 randomized village health promoters using the same training method with which they were trained. Both the rural health workers and village health promoters trained with the Kader approach demonstrated significantly greater improvement in their ability to correctly diagnose and recommend treatment for diarrhea of varying type and severity. These findings suggest that the Kader approach could be applicable to the populations of other developing countries and recommended for large-scale implementation and evaluation in the training of public health workers, village health promoters, and families in Guatemala.

Sciatic cryoneurolysis in rats: a model of sympathetically independent pain. Part 2: Adrenergic pharmacology.

The purpose of this study was to investigate the possibility that sympathetic exacerbation of neuropathic pain activity may be mediated in part by the development of abnormal peripheral adrenergic mechanisms at the site of peripheral nerve injury. We evaluated changes in mechanical stimulation withdrawal thresholds before and after the delivery of selected alpha-adrenergic agonists and antagonists to the immediate area of a prior nerve injury in rats that had developed continuous mechanical allodynia subsequent to sciatic cryoneurolysis (SCN). Allodynia was attenuated (thresholds increased) after administration of the alpha 1 antagonist prazosin, but not the alpha 2 antagonist idazoxan. Similar attenuation occurred with infusions of the alpha 2 agonist dexmedetomidine and at the lowest dose (2.0 micrograms) of the mixed alpha agonist clonidine. In contrast, allodynia was exacerbated (thresholds decreased) by infusion of the highest dose of clonidine (20 micrograms). Infusions of the alpha 2 agonist ST-91, a polar analog of clonidine, did not alter withdrawal thresholds. The findings suggest that a minimal peripheral adrenergic modulation of SCN-induced allodynia occurs via mechanisms that are not localized to the prior injury site. However, overall, the SCN model of neuropathic pain appears to be resistant to adrenergic interventions, providing further evidence that SCN in rats is a model of sympathetically independent pain (SIP).

Gender differences in autotomy following sciatic cryoneurolysis in the rat.

Gender differences reported in nociceptive and nerve injury research should be considered before conclusions about basic pathologic mechanisms are drawn. Holtzman male rats are routinely used in the mononeuropathy model produced by a peripheral nerve freeze lesion, sciatic cryoneurolysis (SCN). SCN reproducibly results in abnormal behaviors which include autotomy, the gnawing and scratching of the affected hindpaw. In the present studies, the incidence and severity of autotomy 1 to 21 days following SCN was compared in male and female Holtzman rats. Female Holtzman rats displayed a decreased incidence and severity of autotomy 7 days and beyond following SCN. This disparity was statistically different at 14 days (p < 0.01) and at 21 days (p < 0.05) by Newman-Keuls test. Morphometric comparison of the sciatic nerve at the lesion site in male and female rats 14 days post-SCN (time of peak autotomy behavior in this model) displayed differences in the fascicular percentage of edema (p < 0.01) and remyelinating axons (p < 0.05) between genders using Student's t-test. However, these percentage values did not correlate with either the incidence or severity of autotomy scores for those animals. Therefore, biochemical differences at and/or proximal to the peripheral nerve freeze lesion may be responsible for mechanisms which generate or relate to autotomy.

Evaluation of a self-help program to reduce alcohol consumption among pregnant women.

This study tested a cognitive-behavioral intervention for reducing alcohol consumption among economically disadvantaged pregnant women. The intervention included a 10-minute educational session and a nine-step self-help manual. Women attending public health maternity clinics completed a screening questionnaire, a pretest questionnaire, were randomly assigned to receive the self-help intervention or usual clinic care, and completed a posttest questionnaire. A higher alcohol quit rate was observed among the intervention participants (88%) than controls (69%). The effect was strongest for "light" drinkers, African-Americans, and non-Protestants. This approach may be useful in clinics where staff time is limited.

Predictive validity of medical student choices of practice location.

We compared University of Alabama medical students' 1980-1981 practice location and specialty preferences with actual practice locations and specialties in 1991 with the following results. (1) Primary care physicians were located mostly in small or large communities, whereas larger than expected numbers of subspecialists practiced in smaller cities. (2) Actual proportions in primary care and surgical subspecialties were less than in earlier preferences; more than expected chose nonsurgical subspecialties. (3) Large city practice locations showed an increase in 1991 at the expense of earlier preferences for medium-sized cities. We suggest that the shift of primary care physicians to larger cities reflects concerns about the financial viability of small town practice, coupled with greater earnings in affluent suburbs. Excess numbers of subspecialists in smaller locations may be due to a perceived oversupply of subspecialists in larger cities.

Comparative histopathology of epidural hydrogel and silicone elastomer catheters following 30 and 180 days implant in the ewe.

New catheter materials, termed Hydrogels, have been developed recently that are stiff until exposed to hydration. The purpose of this study was to compare the 30 and 180 day histopathology of catheters composed of a common silicone elastomer versus a Hydrogel elastomer blend (HEB). Epidural catheters composed of either silicone or HEB were implanted in 19 yearling ewes for either 30 or 180 days. The degree of fibrotic reaction in the epidural space, muscle and subcutaneous tissue was assessed using both histopathology and quantitative imaging analysis. A separate subset of three ewes were implanted with HEB epidural catheters connected to subcutaneously implanted ports through which twice weekly injections of saline were given. There was no evidence of significant neurotoxicology associated with either the silicone or the HEB catheter materials. However, the silicone elastomer group had a quantifiably greater degree of fibrosis than the HEB group of both implant durations. The mean cross sectional area (sq. mm) of epidural pericatheter fibrosis was significantly smaller in the HEB group compared with the silicone group (0.491 in the HEB group and 1.585 in the silicone group at 30 days [P = 0.02] and 0.28 and 1.401 at 180 days [P = 0.0001]. The HEB catheter was easily inserted with standard epidural needles facilitated by the inherent stiffness of the catheter prior to hydration. HEB catheters remained patent throughout 30 days of saline injections per implanted ports. Silicone catheters demonstrated increased fibrosis relative to the HEB catheter material in the epidural space and in subcutaneous tissue.

Comparative spinal neuropathology of hydromorphone and morphine after 9- and 30-day epidural administration in sheep.

Despite extensive clinical use of epidural morphine and to a lesser extent hydromorphone, the neurotoxicologic effects of large-dose epidural administration have not been reported. We compared the impact on behavior, blood and cerebrospinal fluid (CSF) chemistry and hematology, and neuropathology of both epidural morphine (M) and hydromorphone (H) versus preservative-free normal saline (S) given to control animals. Silicone lumbar epidural catheters were implanted in adult sheep and attached to either a subcutaneous port (acute 9-day study) or continuous flow type implantable drug pump (chronic 30-day study) through which the ewes were repeatedly exposed to either the epidural test drug or to similar volumes of saline. The 9-day groups received 5 mL of epidural injections twice daily with the dose incrementally increased as follows: M (n = 6) 40 mg/d, 4 mg/mL; H (n = 6), 16 mg/d, 1.6 mg/mL; S (n = 3), preservative-free normal saline. The 30-day M and H groups were continuously infused epidurally with increasing concentrations eventually augmented with daily epidural boluses: M group (n = 3), 100 mg maximum daily dose, 25 mg/mL maximum concentration; H group (n = 3), 30 mg maximum daily dose, 10 mg/mL maximum concentration; S group (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Suicide in Alabama, 1980 to 1989.

Trends of US suicide rates show great variations among demographic groups over time. Although more attention has been directed to the increasing suicide rate among adolescents, persons aged 65 years and older continue to commit suicide at a higher rate than for any other age group. To examine the recent trend of suicide rates and compare the suicide pattern with that at the national level, we conducted a study using suicide data in Alabama from 1980 to 1989. For all age groups in Alabama in the 1980s, male suicide rates exceeded female rates. Of the four major race-sex groups, nonwhite females are an especially low-risk group, experiencing a rate of about 1.5/100,000 at all ages. There have been remarkable increases in suicide rates in the 1980s for males, especially for nonwhite males in Alabama. The results suggest that high-risk groups to be targeted for interventions are men over age 45 (especially white men over age 65), and divorced and widowed men and women.

Spinal dynorphin immunoreactivity increases bilaterally in a neuropathic pain model.

Increased spinal levels of dynorphin, an endogenous opioid kappa agonist, are seen in models of both chronic and acute hyperalgesia. This study determined the extent and localization of spinal immunoreactive dynorphin following sciatic cryoneurolysis (SCN), a neuropathic pain model produced by a peripheral nerve freeze lesion. SCN results in behaviors associated with neuropathic pain such as autotomy (the gnawing and scratching of the affected limb), touch-evoked and mechanical allodynia, and spontaneous nociceptive behavior. Following SCN, 4 rats that displayed autotomy and 3 rats that did not were randomly chosen for immunohistochemical staining of dynorphin-like immunoreactivity (DLIR). The area of DLIR above a standardized threshold level was quantified in both dorsal horns of each spinal cord section using a computer-assisted image analyzer to express DLIR in pixels. DLIR was observed both ipsilateral and contralateral to the injured peripheral nerve. In addition, the area of DLIR was significantly greater (P = 0.05) in rats that showed autotomy behavior (mean = 52.6 x 10(3) +/- 25.6) compared to rats with no autotomy (mean = 13.8 x 10(3) +/- 4.78). In sharp contrast to the ipsilateral dynorphin increases observed in other neuropathic pain models, we observe a bilateral increase at 21 days following SCN.

The ganglioside GM1 decreases autotomy but not substance P depletion in a peripheral mononeuropathy rat model.

The effect of the ganglioside GM1 on autotomy, a nociceptive behavioral marker for neuropathic pain, and substance P depletion was determined in a rat model of peripheral mononeuropathy, sciatic cryoneurolysis (SCN). SCN is produced by the application of a cryoprobe to the common sciatic nerve using a freeze-thaw-freeze cycle. Due to structural sparing of the nerve, regenerative processes are not precluded. After this peripheral nerve insult, behavioral and neurochemical changes occur that support the use of SCN as a neuropathic pain model. These changes include: autotomy with coincident transient weight loss and paling of eye color suggestive of increased sympathetic activity, spontaneous nociceptive behaviors, touch-evoked allodynia, prolonged mechanical allodynia, ipsilateral decrease of immunoreactive substance P, and increases in spinal cord dynorphin expression. Incidence and severity of autotomy were assessed after the intraperitoneal administration of GM1 (1, 10, and 20 mg/kg) or saline injected daily for 2 days before SCN, the day of surgery, and for 14 days after surgery. In a subset of two rats from each treatment group, transcardiac perfusion was performed and spinal cords were processed for substance P immunoreactivity. GM1 at 10 and 20 mg/kg doses significantly attenuated autotomy as compared with saline-treated rats (P = 0.007 and 0.0001, respectively). However, GM1, at the doses studied, failed to alter the spinal substance P depletion 21 days after SCN. These results indicate that the ganglioside GM1 may have a role in the clinical management of neuropathic pain after peripheral nerve injury.

Neurotoxicology of chronic infusion of the ganglioside GM1 in the ewe: phase I. intrathecal administration.

Gangliosides, including GM1, provide a measure of improved functional recovery after ischemic, toxic, and traumatic brain injuries in animal studies. Since systemically injected GM1 has provided equivocal results in a variety of human neurodegenerative conditions, the possibility exists that intrathecal or intracerebroventricular delivery might provide more effective concentrations along the neuroaxis. In preparation to consider clinical trials, the potential neurotoxicologic effects of chronic intrathecal GM1 were studied in ewes. Preliminary in vitro tests first demonstrated the stability and compatibility of GM1 in implanted pumps. Two groups of adult ewes were then implanted with either Therex or Infusaid continuous flow implantable pumps and chronic intrathecal catheters. Ewes were infused intrathecally with either preservative-free normal saline (n = 5) or GM1 (n = 7) 100 micrograms-10,000 micrograms/d for up to 24 wk. No abnormal behavioral responses were noted. Cerebrospinal fluid analyzed for GM1 concentrations by thin layer chromatography revealed no evidence of GM1 accumulation. After the animals were killed, spinal cords were removed, fixed, sectioned, and stained. Histologic analysis revealed no generalized pattern of neuronal damage, demyelination, gliosis, or axonopathy to distinguish intrathecal normal saline or GM1. In both treated and control groups, the only consistent finding was a pericatheter-associated compression of white matter with axonal dilation, vacuolation, and occasional neuronal loss. Catheter tracts in both groups were also associated with variable leptomeningeal fibroproliferative changes in adjacent dura and pia, at times in conjunction with more generalized duromeningeal thickening. In summary, chronic intrathecal GM1 in doses up to 10 mg/d had no definable neuropathologic consequences.

Conceptual and methodologic problems in the evaluation of a new burn treatment modality.

This article describes and analyzes major conceptual and methodologic problems that occurred during the implementation and evaluation of a new home-based burn treatment modality. Problems described include those of conceptualization, measurement, patient sampling, and follow-up, data collection, and analysis. The origins of each specific problem are discussed along with their effects on the implementation of the project and project outcomes. Solutions for each set of problems are suggested.

Testing an implantable intraspinal drug delivery device in the ewe.

OBJECTIVE: The authors report the use of multiple implanted intraspinal port and catheter systems per test animal to study the in vivo functional characteristics and reliability of a new implantable spinal drug delivery port system. METHODS: Four ewes were each implanted with two epidural and one subarachnoid silicone elastomer catheters at the lumbar level. Each catheter was connected in series to one of three Therex filtered spinal delivery ports implanted subcutaneously in a similar grid pattern in each ewe to facilitate percutaneous identification. Saline (2 ml) was injected 3 times weekly in each port. The ease of injection and behavioral responses were recorded for 207-213 days of implantation until sacrifice/necropsy. RESULTS: All ports functioned reliably during the study. However, injection through two of the four subarachnoid catheters resulted in behavioral withdrawal responses intermittently. This behavioral pattern was much less common after epidural port injections. All four subarachnoid and four of eight epidural port and catheter systems were tested with local anesthetic just before sacrifice. Motor block was observed in three of four subarachnoid and three of four epidural port and catheter systems tested. Integrity of the other four epidural ports was tested by injection of methylene blue at sacrifice. This dye did not distribute in the epidural space in one of the latter four epidural ports (not local anesthetic tested) because of a concentric fibrotic reaction about the catheter. Similar fibrotic reactions surrounded the catheters that failed a functional test with local anesthetic. CONCLUSIONS: The implantable intraspinal port system tested functions reliably under repetitive percutaneous access. However, filtering such ports, though desirable to prevent entry of debris into the spinal canal, did not eliminate pericatheter chronic subarachnoid and epidural reaction. The number of test animals required to test 12 ports chronically was reduced by two-thirds without undue trauma to the individual test subject. Chronic percutaneous injection of an implanted subarachnoid system is feasible but may be associated with behavioral effects similar to that seen with chronic epidural systems. Fibrosis around chronic silicone catheters limited functional utility in one-fourth of the implanted test systems. Further study of the potential reactivity of chronic epidural and subarachnoid catheters is indicated.